記述言語：日本語   掲載種別：研究論文（その他学術会議資料等）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Pathogenic variants of HECW2 have been reported in cases of neurodevelopmental disorder with hypotonia, seizures, and absent language (NDHSAL; OMIM #617268). A novel HECW2 variant (NM_001348768.2:c.4343 T > C,p.Leu1448Ser) was identified in an NDHSAL infant with severe cardiac comorbidities. The patient presented with fetal tachyarrhythmia and hydrops and was postnatally diagnosed with long QT syndrome. This study provides evidence that HECW2 pathogenic variants can cause long QT syndrome along with neurodevelopmental disorders.

DOI： 10.1038/s41439-023-00245-w

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その他リンク： https://www.nature.com/articles/s41439-023-00245-w

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.braindev.2023.02.008

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

The X-linked human glutamate receptor subunit 3 (GRIA3) gene (MIM *305915, Xq25) encodes ionotropic α amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)-type glutamate receptor subunit 3, which mediates postsynaptic neurotransmission. Variants in this gene can cause a variety of neurological disorders, primarily reported in male patients. Here, we report a female patient with developmental and epileptic encephalopathy who carries the novel de novo GRIA3 variant NM_007325.5: c.1982T > C: p.Met661Thr.

DOI： 10.1038/s41439-023-00232-1

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Leigh syndrome is the most genetically heterogenous phenotype of mitochondrial disease. We describe a patient with Leigh syndrome whose diagnosis had not been confirmed because of normal metabolic screening results at the initial presentation. Whole-exome sequencing identified pathogenic variants in NARS2, the gene encoding a mitochondrial asparaginyl-tRNA synthetase. One of the biallelic variants was novel. This highlights the essential role of genetic testing for a definite diagnosis of Leigh syndrome.

DOI： 10.1038/s41439-022-00191-z

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その他リンク： https://www.nature.com/articles/s41439-022-00191-z

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Ovid Technologies (Wolters Kluwer Health)  

DOI： 10.1097/cnd.0000000000000392

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s13256-022-03332-8

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is an autosomal recessive disease caused by biallelic pathogenic ACADM variants. We report a case of an asymptomatic Japanese girl with MCAD deficiency caused by compound heterozygous pathogenic variants (NM_000016.5:c.1040G > T (p.Gly347Val) and c.449_452delCTGA (p.Thr150ArgfsTer4)). Because the MCAD residual activity in lymphocytes of the patient was below the limit of quantification, both variants are likely to cause complete loss of MCAD enzymatic activity.

DOI： 10.1038/s41439-021-00177-3

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その他リンク： https://www.nature.com/articles/s41439-021-00177-3

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.18888/sp.0000001666

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Mutations in DDX3X have recently been identified as a common cause of intellectual disability and congenital anomalies. DDX3X (Xp11.4) encodes the DEAD box RNA helicase that plays an important role in gene regulation, apoptosis, and oncogenesis. Here, we report a case of 6-year-old Japanese girl with a novel variant (NM_001193416.3: c.1574A > G; p.(Tyr525Cys), who exhibited psychomotor retardation, severe constipation, and a recurrent paralytic ileus. This is the second report of severe gastrointestinal symptoms being associated with this disease. This report expands the phenotype caused by DDX3X variants and reveals an important clinical aspect for patients and medical staff.

DOI： 10.1016/j.ejmg.2020.104058

PubMed

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担当区分：筆頭著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：John Libbey Eurotext  

DOI： 10.1684/epd.2020.1187

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記述言語：日本語   掲載種別：研究論文（その他学術会議資料等）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Circulation Society  

BACKGROUND: NT5Egenetic mutations are known to result in calcification of joints and arteries (CALJA), and worldwide, 14 patients from 7 families have been reported.Methods and Results:A total of 5 patients from 2 independent families with CALJA were found in Japan. Of them, 3 complained of intermittent claudication (IC), and 1 suffered from bilateral chronic limb-threatening ischemia (CLTI). Whole-exome sequencing analysis revealed an identical mutation pattern (c.G3C on the exon 1 start codon) that was unique compared withNT5Emutations reported in other countries. CONCLUSIONS: Vascular specialists need to recognize CALJA as a rare cause of ischemic IC and CLTI.

DOI： 10.1253/circj.cj-20-0153

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Usher syndrome type I (USH1) is characterized by congenital, bilateral, profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa. Here, we report a 12-year-old female patient with typical USH1. Targeted panel sequencing revealed compound heterozygous variants of the Cadherin 23 (CDH23) gene, which confirmed the USH1 diagnosis. A novel NM_022124.5:c.130G>A/p.(Glu44Lys) was identified, expanding the mutation spectrum of CDH23.

DOI： 10.1038/s41439-019-0037-y

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その他リンク： http://www.nature.com/articles/s41439-019-0037-y.pdf

担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Genitopatellar syndrome (GPS) is mainly characterized by an absence of patellae, congenital flexion contractures of the lower limbs, psychomotor retardation, and anomalies of the external genitalia and kidneys. We report an 18-year-old female with a novel heterozygous truncating mutation in exon 17 of the KAT6B gene [MC_000010.11:c.3603_3606 del, p.Arg1201fs]. This is the first report of typical GPS in a Japanese individual. The details of our findings may contribute to elucidating the mechanism underlying GPS-specific clinical features.

DOI： 10.1038/s41439-018-0010-1

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その他リンク： https://www.nature.com/articles/s41439-018-0010-1.pdf

記述言語：日本語   出版者・発行元：日本遺伝カウンセリング学会  

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記述言語：日本語   掲載種別：研究論文（大学，研究機関等紀要）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Intellectual disability (ID) is a heterogeneous condition affecting 2-3% of the population, often associated with multiple congenital anomalies (MCA). The genetic cause remains largely unexplained for most cases. To investigate the causes of ID/MCA of unknown etiology in the Japanese population, 645 subjects have been recruited for the screening of pathogenic copy-number variants (CNVs). Two screenings using bacterial artificial chromosome (BAC) arrays were previously performed, which identified pathogenic CNVs in 133 cases (20.6%; Hayashi et al., J. Hum. Genet., 2011). Here, we present the findings of the third screening using a single-nucleotide polymorphism (SNP) array, performed in 450 negative cases from our previous report. Pathogenic CNVs were found in 22 subjects (4.9%), in which 19 CNVs were located in regions where clinical significance had been previously established. Among the 22 cases, we identified PPFIA2 as a novel candidate gene for ID. Analysis of copy-neutral loss of heterozygosity (CNLOH) detected one case in which the CNLOH regions seem to be significant. The SNP array detected a modest fraction of small causative CNVs, which is explained by the fact that the majority of causative CNVs have larger sizes, and those had been mostly identified in the two previous screenings.

DOI： 10.1038/jhg.2015.154

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Whole-exome sequencing (WES) is becoming a standard tool for detecting nucleotide changes, and determining whether WES data can be used for the detection of copy-number variations (CNVs) is of interest. To date, several algorithms have been developed for such analyses, although verification is needed to establish if they fit well for the appropriate purpose, depending on the characteristics of each algorithm. Here, we performed WES CNV analysis using the eXome Hidden Markov Model (XHMM). We validated its performance using 27 rare CNVs previously identified by microarray as positive controls, finding that the detection rate was 59%, or higher (89%) with three or more targets. XHMM can be effectively used, especially for the detection of 4200 kb CNVs. XHMM may be useful for deletion breakpoint detection. Next, we applied XHMM to genetically unsolved patients, demonstrating successful identification of pathogenic CNVs: 1.5-1.9-Mb deletions involving NSD1 in patients with unknown overgrowth syndrome leading to the diagnosis of Sotos syndrome, and 6.4-Mb duplication involving MECP2 in affected brothers with late-onset spasm and progressive cerebral/cerebellar atrophy confirming the clinical suspect of MECP2 duplication syndrome. The possibility of an 'exome-first' approach for clinical genetic investigation may be considered to save the cost of multiple investigations.

DOI： 10.1038/jhg.2014.124

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記述言語：日本語   出版者・発行元：北海道外科学会  

家族性乳癌は同一家系内に多発する乳癌であり、全体の5-10%を占める。原因遺伝子としてBRCA1/2が発見され、遺伝子変異陽性例は遺伝性乳癌卵巣癌症候群(Hereditary Breast and Ovarian Cancer:以下HBOC)と呼ばれている。遺伝子検査の対象は、1)家系内に乳癌症例が集積している、2)若年性乳癌、3)多発癌(両側乳癌、卵巣癌)、4)Triple Negative乳癌、5)男性乳癌などであるが、遺伝子変異陽性例に対するサーベイランス、Risk Reduction Surgery(RRM)、化学的予防であるホルモン療法等の治療、遺伝カウンセリングなど、本疾患に対する体制づくりが希求されている。本稿は家族性乳癌の概要と問題点、更に家族性乳癌の特徴の一つである若年性乳癌について考察した。(著者抄録)

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2014&ichushi_jid=J01375&link_issn=&doc_id=20150325070003&doc_link_id=%2Fdc7hksrg%2F2014%2F005902%2F004%2F0123-0128%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdc7hksrg%2F2014%2F005902%2F004%2F0123-0128%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Purpose: Expression of imprinted genes is regulated by DNA methylation of differentially methylated regions (DMRs). Beckwith-Wiedemann syndrome is an imprinting disorder caused by epimutations of DMRs at 11p15.5. To date, multiple methylation defects have been reported in Beckwith-Wiedemann syndrome patients with epimutations; however, limited numbers of DMRs have been analyzed. The susceptibility of DMRs to aberrant methylation, alteration of gene expression due to aberrant methylation, and causative factors for multiple methylation defects remain undetermined.
Methods: Comprehensive methylation analysis with two quantitative methods, matrix-assisted laser desorption/ionization mass spectrometry and bisulfite pyrosequencing, was conducted across 29 DMRs in 54 Beckwith-Wiedemann syndrome patients with epimutations. Allelic expressions of three genes with aberrant methylation were analyzed. All DMRs with aberrant methylation were sequenced.
Results: Thirty-four percent of KvDMR1-loss of methylation patients and 30% of H19DMR-gain of methylation patients showed multiple methylation defects. Maternally methylated DMRs were susceptible to aberrant hypomethylation in KvDMR1-loss of methylation patients. Biallelic expression of the genes was associated with aberrant methylation. Cis-acting pathological variations were not found in any aberrantly methylated DMR.
Conclusion: Maternally methylated DMRs may be vulnerable to DNA demethylation during the preimplantation stage, when hypomethylation of KvDMR1 occurs, and aberrant methylation of DMRs affects imprinted gene expression. Cis-acting variations of the DMRs are not involved in the multiple methylation defects.

DOI： 10.1038/gim.2014.46

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC NEPHROLOGY  

Background and objectives X-linked Alport syndrome is caused by mutations in the COL4A5 gene. Although many COL4A5 mutations have been detected, the mutation detection rate has been unsatisfactory. Some men with X-linked Alport syndrome show a relatively mild phenotype, but molecular basis investigations have rarely been conducted to clarify the underlying mechanism.
Design, setting, participants, & measurements In total, 152 patients with X-linked Alport syndrome who were suspected of having Alport syndrome through clinical and pathologic investigations and referred to the hospital for mutational analysis between January of 2006 and January of 2013 were genetically diagnosed. Among those patients, 22 patients had suspected splice site mutations. Transcripts are routinely examined when suspected splice site mutations for abnormal transcripts are detected; 11 of them showed expected exon skipping, but others showed aberrant splicing patterns. The mutation detection strategy had two steps: (1) genomic DNA analysis using PCR and direct sequencing and (2) mRNA analysis using RT-PCR to detect RNA processing abnormalities.
Results Six splicing consensus site mutations resulting in aberrant splicing patterns, one exonic mutation leading to exon skipping, and four deep intronic mutations producing cryptic splice site activation were identified. Interestingly, one case produced a cryptic splice site with a single nucleotide substitution in the deep intron that led to intronic exonization containing a stop codon; however, the patient showed a clearly milder phenotype for X-linked Alport syndrome in men with a truncating mutation. mRNA extracted from the kidney showed both normal and abnormal transcripts, with the normal transcript resulting in the milder phenotype. This novel mechanism leads to mild clinical characteristics.
Conclusions This report highlights the importance of analyzing transcripts to enhance the mutation detection rate and provides insight into genotype-phenotype correlations. This approach can clarify the cause of atypically mild phenotypes in X-linked Alport syndrome.

DOI： 10.2215/CJN.04140414

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Coffin-Siris syndrome (CSS) is a congenital disorder characterized by intellectual disability, growth deficiency, microcephaly, coarse facial features, and hypoplastic or absent fifth fingernails and/or toenails. We previously reported that five genes are mutated in CSS, all of which encode subunits of the switch/sucrose non-fermenting (SWI/SNF) ATP-dependent chromatin-remodeling complex: SMARCB1, SMARCA4, SMARCE1, ARID1A, and ARID1B. In this study, we examined 49 newly recruited CSS-suspected patients, and re-examined three patients who did not show any mutations (using high-resolution melting analysis) in the previous study, by whole-exome sequencing or targeted resequencing. We found that SMARCB1, SMARCA4, or ARID1B were mutated in 20 patients. By examining available parental samples, we ascertained that 17 occurred de novo. All mutations in SMARCB1 and SMARCA4 were non-truncating (missense or in-frame deletion) whereas those in ARID1B were all truncating (nonsense or frameshift deletion/insertion) in this study as in our previous study. Our data further support that CSS is a SWI/SNF complex disorder.

DOI： 10.1111/cge.12225

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記述言語：日本語  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Kabuki syndrome is a congenital anomaly syndrome characterized by developmental delay, intellectual disability, specific facial features including long palpebral fissures and ectropion of the lateral third of the lower eyelids, prominent digit pads, and skeletal and visceral abnormalities. Mutations in MLL2 and KDM6A cause Kabuki syndrome. We screened 81 individuals with Kabuki syndrome for mutations in these genes by conventional methods (n=58) and/or targeted resequencing (n=45) or whole exome sequencing (n=5). We identified a mutation in MLL2 or KDM6A in 50 (61.7%) and 5 (6.2%) cases, respectively. Thirty-five MLL2 mutations and two KDM6A mutations were novel. Non-protein truncating-type MLL2 mutations were mainly located around functional domains, while truncating-type mutations were scattered through the entire coding region. The facial features of patients in the MLL2 truncating-type mutation group were typical based on those of the 10 originally reported patients with Kabuki syndrome; those of the other groups were less typical. High arched eyebrows, short fifth finger, and hypotonia in infancy were more frequent in the MLL2 mutation group than in the KDM6A mutation group. Short stature and postnatal growth retardation were observed in all individuals with KDM6A mutations, but in only half of the group with MLL2 mutations. (c) 2013 Wiley Periodicals, Inc.

DOI： 10.1002/ajmg.a.36072

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Approximately 3% of the live-born infants have major dysmorphic features, and about two-thirds of which are observed in the maxillofacial region; however, in many cases, the etiology of the dysmorphic features remains uncertain. Recently, the genome-wide screening of large patient cohorts with congenital disorders has made it possible to discover genomic aberrations corresponding to the pathogenesis. In our analyses of more than 536 cases of clinically undiagnosed multiple congenital anomalies and mental retardation (MR) by microarray-based comparative genomic hybridization, we detected two non-consanguineous unrelated patients with microdeletions at 10p11.23-p12.1, which overlapped for 957 kb, including four protein-coding genes: ARMC4, MPP7, WAC and BAMBI. As the two patients had similar phenotypes; for example, MR and multiple maxillofacial abnormalities including midface retrusion, wide mouth and large tongue, we assessed the phenotypes in detail to define the common features, using quantitative evaluations of the maxillofacial dysmorphism. The concordance of the genetic and phenotypic alterations is a good evidence of a new syndrome. Although an interstitial deletion of 10p is rare, the current study is the first trial to examine precisely the craniofacial characteristics of patients with a heterozygous deletion at 10p11.23-p12.1, and presents good evidence to diagnose potential patients with the same genetic cause. Journal of Human Genetics (2012) 57, 191-196; doi:10.1038/jhg.2011.154; published online 19 January 2012

DOI： 10.1038/jhg.2011.154

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Sotos syndrome is characterized by prenatal and postnatal overgrowth, characteristic craniofacial features and mental retardation. Haploinsufficiency of NSD1 causes Sotos syndrome. Recently, two microdeletions encompassing Nuclear Factor I-X (NFIX) and a nonsense mutation in NFIX have been found in three individuals with Sotos-like overgrowth features, suggesting possible involvements of NFIX abnormalities in Sotos-like features. Interestingly, seven frameshift and two splice site mutations in NFIX have also been found in nine individuals with Marshall-Smith syndrome. In this study, 48 individuals who were suspected as Sotos syndrome but showing no NSD1 abnormalities were examined for NFIX mutations by high-resolution melt analysis. We identified two heterozygous missense mutations in the DNA-binding/dimerization domain of the NFIX protein. Both mutations occurred at evolutionally conserved amino acids. The c.179T > C (p.Leu60Pro) mutation occurred de novo and the c.362G > C (p.Arg121Pro) mutation was inherited from possibly affected mother. Both mutations were absent in 250 healthy Japanese controls. Our study revealed that missense mutations in NFIX were able to cause Sotos-like features. Mutations in DNA-binding/dimerization domain of NFIX protein also suggest that the transcriptional regulation is abnormally fluctuated because of NFIX abnormalities. In individuals with Sotos-like features unrelated to NSD1 changes, genetic testing of NFIX should be considered. Journal of Human Genetics (2012) 57, 207-211; doi:10.1038/jhg.2012.7; published online 2 February 2012

DOI： 10.1038/jhg.2012.7

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Purpose: To determine the significance of PCDH19 mutations in Japanese females with epilepsy and to delineate their phenotypes.
Methods: PCDH19 sequencing analysis was performed in 116 females with various epilepsies, including 97 with Dravet syndrome (83.6%). They were referred for SCN1A analysis, and 52 carried SCN1A mutations.
Results: Seven heterozygous mutations in exon 1 were identified in 7 patients (6.0%): 2 frameshift, 2 nonsense, and 3 missense mutations. One patient was a monozygotic twin, and her sister with mild phenotype carried the same mutation. The main clinical features among these 8 patients included early seizure onset (<= 25 months of age), seizure clusters (7/8), fever-associated seizures (7/8), single seizure type (6/8), and late deterioration of intellect (5/8). Seizure durations were generally up to a few minutes, and only one patient developed status epilepticus once. The main seizure types were generalized tonic clonic (4/8), tonic (3/8) and focal seizures, with (2/8) or without secondary generalization (3/8). Myoclonic, atonic and absence seizures were extremely rare. Two patients had Dravet syndrome (25%), and this proportion was significantly smaller than that in the total subjects (p < 0.01).
Conclusion: PCDH19 mutation is a relatively frequent cause of epilepsy in Japanese females. Dravet syndrome was rare in our cohort. (C) 2011 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.eplepsyres.2011.10.014

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BRESEK/BRESHECK syndrome is a multiple congenital malformation characterized by brain anomalies, intellectual disability, ectodermal dysplasia, skeletal deformities, ear or eye anomalies, and renal anomalies or small kidneys, with or without Hirschsprung disease and cleft palate or cryptorchidism. This syndrome has only been reported in three male patients. Here, we report on the fourth male patient presenting with brain anomaly, intellectual disability, growth retardation, ectodermal dysplasia, vertebral (skeletal) anomaly, Hirschsprung disease, low-set and large ears, cryptorchidism, and small kidneys. These manifestations fulfill the clinical diagnostic criteria of BRESHECK syndrome. Since all patients with BRESEK/BRESHECK syndrome are male, and X-linked syndrome of ichthyosis follicularis with atrichia and photophobia is sometimes associated with several features of BRESEK/BRESHECK syndrome such as intellectual disability, vertebral and renal anomalies, and Hirschsprung disease, we analyzed the causal gene of ichthyosis follicularis with atrichia and photophobia syndrome, MBTPS2, in the present patient and identified an p.Arg429His mutation. This mutation has been reported to cause the most severe type of ichthyosis follicularis with atrichia and photophobia syndrome, including neonatal and infantile death. These results demonstrate that the p.Arg429His mutation in MBTPS2 causes BRESEK/BRESHECK syndrome. © 2011 Wiley Periodicals, Inc.

DOI： 10.1002/ajmg.a.34373

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

The CASK gene encoding a member of the membrane-associated guanylate kinase protein family is highly expressed in the mammalian nervous system of both adults and fetuses, playing several roles in neural development and synaptic function. Recently, CASK aberrations caused by both mutations and deletions have been reported to cause severe mental retardation (MR), microcephaly and disproportionate pontine and cerebellar hypoplasia (MICPCH) in females. Here, mutations and copy numbers of CASK were examined in ten females with MR and MICPCH, and the following changes were detected: nonsense mutations in three cases, a 2-bp deletion in one case, mutations at exon-intron junctions in two cases, heterozygous deletions encompassing CASK in two cases and interstitial duplications in two cases. Except for the heterozygous deletions, each change including the intragenic duplications potentially caused an aberrant transcript, resulting in CASK null mutations. The results provide novel mutations and copy number aberrations of CASK, causing MR with MICPCH, and also demonstrate the similarity of the phenotypes of MR with MICPCH regardless of the CASK mutation.

DOI： 10.1007/s00439-011-1047-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

BRESEK/BRESHECK syndrome is a multiple congenital malformation characterized by brain anomalies, intellectual disability, ectodermal dysplasia, skeletal deformities, ear or eye anomalies, and renal anomalies or small kidneys, with or without Hirschsprung disease and cleft palate or cryptorchidism. This syndrome has only been reported in three male patients. Here, we report on the fourth male patient presenting with brain anomaly, intellectual disability, growth retardation, ectodermal dysplasia, vertebral (skeletal) anomaly, Hirschsprung disease, low-set and large ears, cryptorchidism, and small kidneys. These manifestations fulfill the clinical diagnostic criteria of BRESHECK syndrome. Since all patients with BRESEK/BRESHECK syndrome are male, and X-linked syndrome of ichthyosis follicularis with atrichia and photophobia is sometimes associated with several features of BRESEK/BRESHECK syndrome such as intellectual disability, vertebral and renal anomalies, and Hirschsprung disease, we analyzed the causal gene of ichthyosis follicularis with atrichia and photophobia syndrome, MBTPS2, in the present patient and identified an p. Arg429His mutation. This mutation has been reported to cause the most severe type of ichthyosis follicularis with atrichia and photophobia syndrome, including neonatal and infantile death. These results demonstrate that the p. Arg429His mutation in MBTPS2 causes BRESEK/BRESHECK syndrome. (C) 2011 Wiley Periodicals, Inc.

DOI： 10.1002/ajmg.a.34373

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Axial spondylometaphyseal dysplasia (SMD) (OMIM 602271) is an uncommon skeletal dysplasia characterized by metaphyseal changes of truncal-juxtatruncal bones, including the proximal femora, and retinal abnormalities. The disorder has not attracted much attention since initially reported; however, it has been included in the nosology of genetic skeletal disorders [Warman et al. (2011); Am J Med Genet Part A 155A:943-968] in part because of a recent publication of two additional cases [Isidor et al. (2010); Am J Med Genet Part A 152A:1550-1554]. We report here on the clinical and radiological manifestations in seven affected individuals from five families (three sporadic cases and two familial cases). Based on our observations and Isidor's report, the clinical and radiological hallmarks of axial SMD can be defined: The main clinical findings are postnatal growth failure, rhizomelic short stature in early childhood evolving into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection. Impaired visual acuity comes to medical attention in early life and function rapidly deteriorates. Retinal changes are diagnosed as retinitis pigmentosa or pigmentary retinal degeneration on fundoscopic examination and cone-rod dystrophy on electroretinogram. The radiological hallmarks include short ribs with flared, cupped anterior ends, mild spondylar dysplasia, lacy iliac crests, and metaphyseal irregularities essentially confined to the proximal femora. Equally affected sibling pairs of opposite gender and parental consanguinity are strongly suggestive of autosomal recessive inheritance. (C) 2011 Wiley-Liss, Inc.

DOI： 10.1002/ajmg.a.34192

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Autosomal dominant nocturnal frontal lobe epilepsy is a familial partial epilepsy syndrome and the first human idiopathic epilepsy known to be related to specific gene defects. Clinically available molecular genetic testing reveals mutations in three genes, CHRNA4, CHRNB2 and CHRNA2. Mutations in CHRNA4 have been found in families from different countries; the Ser280Phe in an Australian, Spanish, Norwegian and Scottish families, and the Ser284Leu in a Japanese, Korean, Polish and Lebanese families. Clear evidence for founder effect was not reported among them, including a haplotype study carried out on the Australian and Norwegian families. Japanese and Koreans, because of their geographical closeness and historical interactions, show greater genetic similarities than do the populations of other countries where the mutation is found. Haplotype analysis in the two previously reported families showed, however, independent occurrence of the Ser284Leu mutation. The affected nucleotide was highly conserved and associated with a CpG hypermutable site, while other CHRNA4 mutations were not in mutation hot spots. Association with a CpG site accounts for independent occurrence of the Ser284Leu mutation. Journal of Human Genetics ( 2011) 56, 609-612; doi:10.1038/jhg.2011.69; published online 14 July 2011

DOI： 10.1038/jhg.2011.69

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

All patients with terminal deletion of chromosome 15q have been reported to show intrauterine growth retardation, postnatal growth retardation, abnormal facial appearance and developmental delay. Haploinsufficiency of IGF1R was considered to be responsible for these symptoms. However, it is difficult to explain other symptoms seen in some of the patients, such as congenital heart defects by the absence of IGF1R alone.
Here, we reported a patient with congenital heart defects and a 5.78 Mb terminal deletion of chromosome 15q detected by array-CGH. Among the patients reported to share congenital heart defects and terminal deletion of chromosome 15q, our patient had the smallest deletion. Evaluating the deletion map, NR2F2 was considered a candidate gene contributing to congenital heart defects in patients with terminal deletion of chromosome 15q. (C) 2010 Elsevier Masson SAS. All rights reserved.

DOI： 10.1016/j.ejmg.2010.12.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Recent advances in the analysis of patients with congenital abnormalities using array-based comparative genome hybridization (aCGH) have uncovered two types of genomic copy-number variants (CNVs); pathogenic CNVs (pCNVs) relevant to congenital disorders and benign CNVs observed also in healthy populations, complicating the screening of disease-associated alterations by aCGH. To apply the aCGH technique to the diagnosis as well as investigation of multiple congenital anomalies and mental retardation (MCA/MR), we constructed a consortium with 23 medical institutes and hospitals in Japan, and recruited 536 patients with clinically uncharacterized MCA/MR, whose karyotypes were normal according to conventional cytogenetics, for two-stage screening using two types of bacterial artificial chromosome-based microarray. The first screening using a targeted array detected pCNV in 54 of 536 cases (10.1%), whereas the second screening of the 349 cases negative in the first screening using a genome-wide high-density array at intervals of approximately 0.7Mb detected pCNVs in 48 cases (13.8%), including pCNVs relevant to recently established microdeletion or microduplication syndromes, CNVs containing pathogenic genes and recurrent CNVs containing the same region among different patients. The results show the efficient application of aCGH in the clinical setting. Journal of Human Genetics (2011) 56, 110-124; doi: 10.1038/jhg.2010.129; published online 28 October 2010

DOI： 10.1038/jhg.2010.129

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

We report the case of a female Japanese infant who was diagnosed with incontinentia pigmenti (IP) on the basis of the clinical and pathological findings of characteristic skin lesions and the detection of deletion in the nuclear factor-kappa B essential modulator gene at Xq28. The patient developed repetitive seizures at the age of 7 months when she was diagnosed with acute disseminated encephalomyelitis (ADEM), an inflammatory demyelinating disease of the central nervous system that often occurs after vaccination or infection. The causative infectious agent in this patient seemed to be Mycoplasma pneumoniae because of the increased titer of its serum antibody and the detection of its DNA in the initial cerebrospinal fluid sample. This patient showed significant improvement on receiving immunosuppressive therapy with corticosteroids. This is the second case report presenting an IP patient Susceptible to ADEM, and therefore, ADEM should be considered early in the differential diagnosis of acute neurological illness for IP patients. (C) 2008 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.braindev.2008.08.010

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：INT PEDIATRIC RESEARCH FOUNDATION, INC  

IGF-II associates with feto-placental growth in rodent and human. determined three tag-single nucleotide polymorphisms (SNPs) to investigate haplotype frequency of IGF2 relative to size at birth in 134 healthy Japanese infants. In addition, a total of 276 healthy infants were investigated to determine whether common genetic variation of IGF2 might contribute to feto-placental growth Using haplotype analysis. Further, quantitative methylation analysis of the IGF2/HI9 wits performed using the MassARRAY Compact system. In the initial study,. the frequency of haplotype CTG front the paternal allele in small for date (SFD) infants was significantly higher than that in non-SFD infants (p = 0.03). In second Study, the CTG haplotype infants exhibited significantly lower birth length, weight. and placental weight Compared with non-CTG infants. Further, the number of infants less than - 1,5 SD (SD) birth weight in CTG haplotype was higher than those if non-CTG infants. There was no significant difference in the methylation status of HI9/IGF2 in the two haplotypes. In conclusion, inheriting the IGF2 CTG haplotype front I paternal allele results ill reduced feto-placental growth. but it is not associated with the methylation Status of IGF2/HI9. (Pediatr Res 66: 135-139, 2009)

DOI： 10.1203/PDR.0b013e3181a9e818

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN ATHEROSCLEROSIS SOC  

Aim: We previously identified a quantitative trait locus (QTL) on rat chromosome 5 that appeared to be primarily controlled by the sympathetic nervous system. Because sympathetic overactivity is related to hypertension, solute carrier family 6, member 9 (SLC6A9) is a candidate gene for the connection of this QTL with blood pressure regulation. In the present study, we therefore explored the role of SLC6A9 genetic variations in human essential hypertension (EH).
Methods: We evaluated three single nucleotide polymorphisms (SNPs) (rs2286245, rs3791124 and rs2486001) in 758 essential hypertension patients and 726 controls. Polymorphism-related genotypes were determined with TaqMan assays.
Results: The allelic frequency of rs2286245 (C versus T, p=0.032) showed significant differences between EH and normotensive controls (NT) groups. The genotypic distribution of rs3791124 in its dominant model (AA + GA versus GG, p = 0.027) also showed significant differences between EH and NT groups. The genotype and allele distributions of rs2486001 did not exhibit any significant differences.
Conclusion: We found an association between SLC6A9 gene polymorphisms and essential hypertension in a Japanese population, suggesting that SLC6A9 is a susceptibility locus for essential hypertension.

DOI： 10.5551/jat.E125

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Background: The underlying genetic abnormalities of rare familial idiopathic epilepsy have been identified, Such as mutation in KCNQ2, a K(+) channel gene. Yet, few genetic abnormalities have been reported for commoner epilepsy, i.e., sporadic idiopathic epilepsy, which share a phenotype similar to those of familial epilepsy. Objective: To search for the genetic cause of seizures in it girl with the diagnosis of non-familial benign neonatal convulsions, and define the consequence of the genetic abnormality identified. Methods: Genetic abnormality was explored within candidate genes for benign familial neonatal and infantile convulsions, such as KCNQ2, 3. 5, KCNE2, SCN1A and SCN2A. The electrophysiological properties of the channels harboring the identified Mutation were examined. Western blotting and immunostaining were employed to characterize the expression and intracellular localization of the mutant channel molecules. Results: A novel heterozygous Mutation (c.910-2delTTC or TTT, Phe304del) of KCNQ2 was identified ill the patient. The mutation was de novo verified by parentage analysis. The mutation wits associated with impaired functions of KCNQ K(+) channel. The mutant channels were expressed on the cell surface. Conclusion: The mutant Phe304del of KCNQ2 leads to null function or the KCNQ K(+) channel but the mutation does not after proper channel sorting onto the cell membrane. Our findings indicate that the genes responsible for rare inherited forms of idiopathic epilepsy could be also involved in sporadic forms of idiopathic epilepsy and expand Our notion of the involvement of molecular mechanisms in the more common forms of idiopathic epilepsy. (C) 2008 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.braindev.2008.05.010

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-LISS  

Here we report on a 1-year-old Japanese girl with psychomotor retardation, bilateral congenital cortical opacity and bilateral postaxial polysyndactyly of the feet. Although she had a normal female karyotype, our in-house bacterial artificial chromosome (BAC)-based array-CGH analysis successfully detected at least a 2.7-Mb heterozygous deletion at 1.1q22.1-q22.3 harboring 18 protein-coding genes. Among the genes, BMP4 was a candidate for the gene causing the abnormalities of both the eye and digits. It was previously reported that the BMP family was correlated with the morphogenesis of digits and ocular development, and Bmp4 heterozygous null mice revealed skeletal abnormalities including polydactyly and ocular anterior segment abnormalities. Patients with a deletion including BMP4 also hadabnormalities of the eye and digits. These previous reports support that a haplo-insufficiency of the BMP4 gene likely caused the congenital ocular and digit abnormalities. Moreover, among the other genes contained in the deletion; GMFB is a candidate for the gene responsible, for the psychomotor retardation. (C) 2008 Wiley-Liss. Inc,

DOI： 10.1002/ajmg.a.32519

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-LISS  

Here we report on a 5-year-old Japanese girl with developmental dealy and microcephaly. Although she had a normal karyotype, a bacterial artifical chromosome-based array-comparative genome hybridization analysis detected a de novo 4.0-Mb heterozygous deletion at Xp11.3-p11.4 harboring nine genes. By comparison with a healthy carrier mother of a boy with atypical Norrie disease having a smaller deletion in the same region. we excluded four genes as candidates whose haploinsufficiency would be causative for developmental delay. Among the other five genes, CASK seems to be the most likely candidate for a causative gene, because it is strongly expressed in fetal brain and plays important roles in neural development and synaptic function. We confirmed that the expression of CASK mRNA was decreased in the patient compared with healthy controls and the patient's X-chromosomal inactivation was not skewed. These results suggested that the genetic deletion of CASK results in haploinsufficiency, which might be causative for the patient's developmental delay or mental retardation. (C) 2008 Wiley-Liss, Inc.

DOI： 10.1002/ajmg.a.32433

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

BACKGROUND We have earlier identified a quantitative trait locus (QTL) on rat chromosome 5 that appears to be primarily under the control of the sympathetic nervous system. Because sympathetic overactivity is related to both hypertension and insulin resistance, FABP3 is a candidate gene for the link between this QTL and blood pressure regulation. In this study, therefore, we explored the role of FABP3 genetic variations in essential hypertension (EH) in humans.
METHODS We evaluated two single-nucleotide polymorphisms (SNPs) (rs2279885 and rs2271072) in 758 patients with EH and 726 controls. Polymorphism-related genotypes were determined using TaqMan assays, while haplotypes were estimated from the genotype data.
RESULTS The frequencies of occurrence of the G allele of rs2279885 and the C allele of rs2271072 were significantly higher in subjects with EH than in normotensive (NT) subjects (P = 0.0339, P = 0.0209, respectively). However, the genotype distributions did not exhibit any significant differences.
CONCLUSION We found an association between FABP3 gene polymorphisms and EH in a Japanese population, thereby suggesting that FABP3 is a susceptibility locus for EH.

DOI： 10.1038/ajh.2008.40

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Background Essential hypertension is a complex disorder that results from the interaction of a number of susceptibility genes and environmental factors. The TNFRSF4 (tumor necrosis factor receptor superfamily, member 4) gene was one of the genes that showed altered renal expression in long-term salt loading in mice. Moreover, association of the TNFRSF4 and TNFSF4 (tumor necrosis factor (ligand) superfamily, member 4) genes with myocardial infarction was recently reported. Since essential hypertension is a well-known risk factor for myocardial infarction, we hypothesized that TNFRSF4 could be a susceptibility gene for essential hypertension.
Methods We performed a case -control study of TNFRSF4 in two independent population.
Results Extensive investigation of single nucleotide polymorphisms of the entire gene suggested that it resided in one linkage disequilibrium block, and four single nucleotide polymorphisms in the 50 flanking region sufficiently represented major haplotypes. In the combined population, the frequency of the most frequent haplotype, C-C-A- A, was significantly lower (P = 8.07 X 10(-5)) and that of the second most frequent haplotype, C-T-G-A, was significantly higher (P = 6.07 X 10(-4)) in hypertensive subjects than in control subjects. This difference was observed only in female patients. The C-T-G-A haplotype showed a lower promoter activity than other haplotypes, suggesting a relationship with disease susceptibility.
Conclusion Our results suggest that TNFRSF4 is a female-specific susceptible gene for essential hypertension.

DOI： 10.1097/HJH.0b013e3282f6a65e

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ENDOCRINE SOC  

Context: Neonatal diabetes mellitus ( NDM) is classified clinically into a transient form ( TNDM), in which insulin secretion recovers within several months, and a permanent form ( PNDM), requiring lifelong medication. However, these conditions are genetically heterogeneous.
Objective: Our objective was to evaluate the contribution of the responsible gene and delineate their clinical characteristics.
Patients and Methods: The chromosome 6q24 abnormality and KCNJ11 and ABCC8 mutations were analyzed in 31 Japanese patients ( 16 with TNDM and 15 with PNDM). Moreover, FOXP3 and IPF1 mutations were analyzed in a patient with immune dysregulation, polyendocrinopathy, enteropathy X- linked syndrome and with pancreatic agenesis, respectively.
Results: A molecular basis for NDM was found in 23 patients: 6q24 in eleven, KCNJ11 in nine, ABCC8 in two, and FOXP3 in one. All the patients with the 6q24 abnormality and two patients with the KCNJ11 mutation proved to be TNDM. Five mutations were novel: two ( p. A174G and p. C166Y) in KCNJ11, two ( p. A90V and p. N1122D) in ABCC8, and one ( p. P367L) in FOXP3. Comparing the 6q24 abnormality and KCNJ11 mutation, there were some significant clinical differences: the earlier onset of diabetes, the lower frequency of diabetic ketoacidosis at onset, and the higher proportion of the patients with macroglossia at initial presentation in the patients with 6q24 abnormality. In contrast, two patients with the KCNJ11 mutations manifested epilepsy and developmental delay.
Conclusions: Both the 6q24 abnormality and KCNJ11 mutation are major causes of NDM in Japanese patients. Clinical differences between them could provide important insight into the decision of which gene to analyze in affected patients first.

DOI： 10.1210/jc.2007-0486

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：UNIV CHICAGO PRESS  

The C syndrome is characterized by trigonocephaly and associated anomalies, such as unusual facies, psychomotor retardation, redundant skin, joint and limb abnormalities, and visceral anomalies. In an individual with the C syndrome who harbors a balanced chromosomal translocation, t(3; 18)(q13.13; q12.1), we discovered that the TACTILE gene for CD96, a member of the immunoglobulin superfamily, was disrupted at the 3q13.3 breakpoint. In mutation analysis of nine karyotypically normal patients given diagnoses of the C or C-like syndrome, we identified a missense mutation (839C -> T, T280M) in exon 6 of the CD96 gene in one patient with the C-like syndrome. The missense mutation was not found among 420 unaffected Japanese individuals. Cells with mutated CD96 protein (T280M) lost adhesion and growth activities in vitro. These findings indicate that CD96 mutations may cause a form of the C syndrome by interfering with cell adhesion and growth.

DOI： 10.1086/522014

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-LISS  

We report on a 2-year-old Japanese girl with Cornelia-de Lange syndrome (CdLS) who had mental and growth retardation, together with characteristic facial anomalies and mild extremity malformations. She had a balanced chromosomal translocation, 46,XX,t(5;13)(p13-1;q12.1) de novo. Surprisingly, this was the same translocation that had provided a clue to the identification of a major causative gene for CdLS, NIPBL [Krantz et al., 2004; Tonkin et al., 2004]. Using fluorescence in situ hybridization (FISH), the breakpoint was confirmed to lie within NIPBL at 5p13,1. Furthermore, array-based comparative genomic hybridization (array-CGH) demonstrated a cryptic I-Mb deletion harboring six known genes at 1q25-q31.1. A FISH analysis of her parents confirmed that the deletion was de novo. Although patients with interstitial deletions at 1q are rare, some of their features were similar to those observed in our patient, indicating that her clinical manifestations are likely to be affected by not only the disruption of NIPBL but also the concomitant microdeletion at 1q25-q31.1. The present case suggests that array-CGH can uncover cryptic genomic aberrations affecting atypical phenotypes even in wellknown congenital disorders. (c) 2007 Wiley-Liss, Inc.

DOI： 10.1002/ajmg.a.31737

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER TOKYO  

The human chromosome X is closely associated with congenital disorders and mental retardation (MR), because it contains a significantly higher number of genes than estimated from the proportion in the human genome. We constructed a high-density and high-resolution human chromosome X array (X-tiling array) for comparative genomic hybridization (CGH). The array contains a total of 1,001 bacterial artificial chromosome (BACs) throughout chromosome X except pseudoautosomal regions and two BACs specific for Y. In four hybridizations using DNA samples from healthy males, the ratio of each spotted DNA was scattered between -3SD and 3SD, corresponding to a log(2) ratio of -0.35 and 0.35, respectively. Using DNA samples from patients with known congenital disorders, our X-tiling array was proven to discriminate one-copy losses and gains together with their physical sizes, and also to estimate the percentage of a mosaicism in a patient with mos 45,X[13]/46,X,r(X)[7]. Furthermore, array-CGH in a patient with atypical Schinzel-Giedion syndrome disclosed a 1.1-Mb duplication at Xq22.3 including a part of the IL1RAPL2 gene as a likely causative aberration. The results indicate our in-house X-tiling array to be useful for the identification of cryptic copy-number aberrations containing novel genes responsible for diseases such as congenital disorders and X-linked MR.

DOI： 10.1007/s10038-007-0127-4

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記述言語：英語   出版者・発行元：5  

Cardio-facio-cutaneous (CFC) syndrome is a multiple congenital anomaly/mental retardation syndrome characterized by a distinctive facial appearance, ectodermal abnormalities, and heart defects. Clinically, it overlaps with both Noonan syndrome and Costello syndrome, which are caused by mutations in 2 genes that encode molecules of the RAS/MAPK (mitogen activated protein kinase) pathway (PTPN11 and HRAS, respectively). Recently, mutations in KRAS, BRAF, and MEK1/2 have been identified in patients with CFC syndrome. Somatic mutations in KRAS and BRAF have been identified in various tumors. In contrast, the association with malignancy has not been noticed in CFC syndrome. Here we report a 9-year-old boy diagnosed with CFC syndrome and acute lymphoblastic leukemia. Sequencing analysis of the entire coding region of KRAS and BRAF showed a de novo germline BRAF E501G (1502A-->G) mutation. Molecular diagnosis and careful observations should be considered in children with CFC syndrome because they have germline mutations in proto-oncogenes and might develop malignancy.

DOI： 10.1097/MPH.0b013e3180547136

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記述言語：英語   出版者・発行元：8  

Cardio-facio-cutaneous (CFC) syndrome is a multiple congenital anomaly/mental retardation syndrome characterized by heart defects, a distinctive facial appearance, ectodermal abnormalities and mental retardation. Clinically, it overlaps with both Noonan syndrome and Costello syndrome, which are caused by mutations in two genes, PTPN11 and HRAS, respectively. Recently, we identified mutations in KRAS and BRAF in 19 of 43 individuals with CFC syndrome, suggesting that dysregulation of the RAS/RAF/MEK/ERK pathway is a molecular basis for CFC syndrome. The purpose of this study was to perform comprehensive mutation analysis in 56 patients with CFC syndrome and to investigate genotype-phenotype correlation. We analyzed KRAS, BRAF, and MAP2K1/2 (MEK1/2) in 13 new CFC patients and identified five BRAF and one MAP2K1 mutations in nine patients. We detected one MAP2K1 mutation in three patients and four new MAP2K2 mutations in four patients out of 24 patients without KRAS or BRAF mutations in the previous study [Niihori et al., 2006]. No mutations were identified in MAPK3/1 (ERK1/2) in 21 patients without any mutations. In total, 35 of 56 (62.5%) patients with CFC syndrome had mutations (3 in KRAS, 24 in BRAF, and 8 in MAP2K1/2). No significant differences in clinical manifestations were found among 3 KRAS-positive patients, 16 BRAF-positive patients, and 6 MAP2K1/2-positive patients. Wrinkled palms and soles, hyperpigmentation and joint hyperextension, which have been commonly reported in Costello syndrome but not in CFC syndrome, were observed in 30-40% of the mutation-positive CFC patients, suggesting a significant clinical overlap between these two syndromes.

DOI： 10.1002/ajmg.a.31658

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Inactivating mutations in the follicle-stimulating hormone receptor (FSHR) gene have been reported to cause hereditary hypergonadotropic ovarian failure. It has been found recently that the FSHR knockout mouse exhibits hypertension. The aim of the present study was to investigate the association between polymorphisms in the human FSHR gene and essential hypertension (EH) by using single nucleotide polymorphisms (SNPs). We selected 5 SNPs in the gene (rs1394205, rs2055571, rs11692782, rs1007541, and rs2268361) and performed 2 genetic case-control studies in different populations. A confirmative case-control study was performed using 1035 EH patients and 1058 age-matched controls. Transcriptional activities were measured with a luciferase assay system. The first case-control study found that the A allele of rs1394205 was significantly higher in EH females (P=0.010). In addition, in the confirmative case-control study, there was a significant difference for this SNP between female normotensive subjects (44.5%) and EH patients (50.7%) (P=0.043). Multiple logistic regression analysis in female subjects also revealed a significant association of subjects with the A allele of rs1394205 with EH (P=0.033), with the odds ratio calculated as 1.68 (95% CI: 1.04 to 2.73). Transcriptional activity of the A allele was 56 +/- 8% (mean +/- SD) of that observed for the G-type allele (P=0.001). Serum estradiol levels were significantly lower in patients with the A/A genotype than in patients without the A/A genotype (P=0.004). The SNP in the 5'-untranslated region of the FSHR gene affects levels of transcriptional activity and is a susceptibility mutation of EH in women.

DOI： 10.1161/01.HYP.0000233877.84343.d7

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担当区分：筆頭著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   出版者・発行元：WILEY-LISS  

DOI： 10.1002/ajmg.a.31164

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Study Design. A retrospective study of radiographic and clinical findings of spondylocostal dysostosis.
Objective. To determine the features of spondylocostal dysostosis diagnosed using consistent diagnostic criteria.
Summary of Background Data. To our knowledge, no clear definition of spondylocostal dysostosis exists, and little information is available regarding its clinical or radiographic features.
Methods. We defined spondylocostal dysostosis as a congenital spinal disorder consisting of >= 2 vertebral anomalies associated with rib anomalies, without crab-like chest. For 30 patients, including 12 males and 18 females, who met these criteria, we evaluated vertebral and rib anomalies, birth and present body height, and associated anomalies. There were only 2 familial cases.
Results. Features of spondylocostal dysostosis were: (1) anomalies involved the thoracic region in all cases; many also involved the cervical spine; (2) most patients had >= 4 vertebral anomalies; (3) frequent vertebral anomalies were butterfly vertebra, hemivertebra, complete block, and unilateral bar, which were associated with both rib absence and fusion; (4) short stature was not always present at birth; and (5) complete block was 1 factor identified as being related to short stature after 12 years of age.
Conclusion. Several features of sporadic spondylocostal dysostosis disorder were determined, including new findings related to body height.

DOI： 10.1097/01.brs.0000208166.61618.8f

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MOSBY-ELSEVIER  

CHD7 gene mutations were identified in 17 (71%) of 24 children clinically diagnosed to have CHARGE syndrome (C, coloboma of the iris or retina; H, heart defects; A, atresia of the choanae; R, retardation of growth and/or development; G, genital anomalies; and E, car abnormalities). Colobomata, hearing loss, laryngomalacia, and vestibulo-cochlear defect were prevalent. Molecular testing for CHD7 enables an accurate diagnosis and provides health anticipatory guidance and genetic counseling to families with CHARGE syndrome.

DOI： 10.1016/j.jpeds.2005.10.044

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-LISS  

Array using 2,173 BAC clones covering the whole human genome has been constructecl. All clones spottecl were confirmed to show a Unique signal at the predicted chromosomal location by FISH analysis in our laboratory. A total of 30 individuals with idiopathic mental retardation (MR) were analyzed by comparative genomic hybridization Using this array. Three deletions, one duplication, and one unbalanced translocation could be detected in five patients, which are likely to contribute to MR. The constructed array was shown to be an efficient tool for the detection of pathogenic genomic rearrangements in MR patients as well as copy number polymorphisms (CPN's). (c) 2006 Wiley-Liss, Inc.

DOI： 10.1002/ajmg.a.31098

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：4  

Mutations in the CREBBP (CREB-binding protein gene) cause Rubinstein-Taybi syndrome (RSTS). At present, however, genetic testing of CREBBP is not commonly applied in clinical settings because the currently available assays are technically and financially demanding, mainly because of the size of the gene. In the present study, we took advantage of a highly sensitive and specific, automated denaturing high-performance liquid chromatography (DHPLC) technique. First, we developed a DHPLC-based protocol to analyze the entire coding region of CREBBP. Second, we analyzed genetic samples from 21 RSTS patients using DHPLC. The coding region was amplified by 41 primer pairs, all of which have the same cycling conditions, aliquoted on a 96-well format PCR plate. In this manner, all the exons were simultaneously amplified using a single block in a PCR machine. We then wrote a computer script to analyze all the PCR amplicons generated from various portions of the CREBBP gene in a serial manner at optimized conditions determined individually for each amplicon. Heterozygous CREBBP mutations were identified in 12 of the 21 patients: five frameshift mutations, three nonsense mutations, two splice-site mutations, and two missense mutations. The resulting detection rate of 57% was comparable to the outcome of previous studies. The relatively high detection rate in the present study demonstrates the enhanced sensitivity of the DHPLC-based mutation analysis, as exemplified by mutation analyses of other genes. The implementation of similar methodologies for other dysmorphic syndromes will help medical geneticists to confirm their clinical impressions and to provide accurate genetic counseling for patients and their families.

DOI： 10.1111/j.1741-4520.2005.00081.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Purpose: We tested the hypothesis that Sotos syndrome (SoS) due to the common deletion is a contiguous gene syndrome incorporating plasma coagulation factor twelve (FXII) deficiency. The relationship between FXII activity and the genotype at a functional polymorphism of the FXII gene was investigated.
Methods: A total of 21 patients including those with the common deletion, smaller deletions, and point mutations, and four control individuals were analyzed. We examined FXII activity in patients and controls, and analyzed their FXII 46C/T genotype using direct DNA sequencing.
Results: Among 10 common deletion patients, seven patients had lower FXII activity with the 46T allele of the FXII gene, whereas three patients had normal FXII activity with the 46C allele. Two patients with smaller deletions, whose FXII gene is not deleted had low FXII activity, but one patient with a smaller deletion had normal FXII. Four point mutation patients and controls all had FXII activities within the normal range.
Conclusion: FXII activity in SoS patients with the common deletion is predominantly determined by the functional polymorphism of the remaining hemizygous FXII allele. Thus, Sotos syndrome is a contiguous gene syndrome incorporating coagulation factor twelve (FXII) deficiency.

DOI： 10.1097/01.GIM.0000177419.43309.37

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：日本語  

著者版ルポイド過形成症患児で,エクソン7のコドン258が終止コドンに変わる変異(Q258X)を持つ21例を対象とし,Q258X変異が創始者効果を持つか検討した.内訳は,Q258X変異のホモ接合体患児が10例で,Q258X変異との複合型ヘテロ接合体患児が11例である.正常コントロールには,正常人96例を用いた.3SNPsと3マイクロサテライトマーカー計6つのマーカーで構成されるハプロタイプは,Q258X変異を持つ患児の72.9%において共通でありQ258X変異の周辺50kbにおいて保存されていることが明らかになった.Q258X変異を持つハプロタイプTGC-311-323-313は,日本人集団において多いハプロタイプでないばかりか,正常96例では検出されない稀なハプロタイプであることが判明した.このことは,Q258X変異の共通祖先が,日本人集団由来ではなく,その他の地域から由来していることが示唆された

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：B M J PUBLISHING GROUP  

DOI： 10.1136/jmg.2003.014803

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER-VERLAG  

Shwachman-Diamond syndrome (SDS; OMIM 260400) is an autosomal recessive disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction and metaphyseal chondrodysplasia. SDS is caused by mutations in SBDS, an uncharacterized gene. A previous study in SDS patients largely of European ancestry found that most SBDS mutations occurred within a similar to240-bp region of exon 2 and resulted from gene conversion due to recombination with a pseudogene, SBDSP. It is unknown, however, whether these findings are applicable to other ethnic groups. To address this question, we examined SBDS mutations in six Japanese families with SDS by direct sequencing. We identified compound heterozygous mutations in four families: two were recurrent (96-97insA, 258+2T>C), and three were novel [292-295delAAAG, (183-184TA>CT +201A>G), (141C>T+183-184TA>CT+201A>G)] mutations. Most of these mutations also appear to result from gene conversion, but the conversion events occurred at various sites between intron 1 and exon 3. Thus, gene conversion mutations in SBDS are common to different ethnic groups, but they are not confined to a limited region of the gene.

DOI： 10.1007/s00439-004-1081-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：B M J PUBLISHING GROUP  

DOI： 10.1136/jmg.2003.013722

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-LISS  

Sotos syndrome (SoS) is an autosomal dominant overgrowth syndrome with characteristic craniofacial dysmorphic features and various degrees of mental retardation. We previously showed that haploinsufficiency of the NSD1 gene is the major cause of SoS, and submicroscopic deletions at 5q35, including NSD1, were found in about a half (20/42) of our patients examined. Since the first report, an additional 70 SoS cases consisting of 53 Japanese and 17 non-Japanese have been analyzed. We found 50 microdeletions (45%) and 16 point mutations (14%) among all the 112 cases. A large difference in the frequency of microdeletions between Japanese and non Japanese patients was noted: 49 (52%) of the 95 Japanese patients and only one (6%) of the 17 non-Japanese had microdeletions. A sequence-based physical map was constructed to characterize the microdeletions. Most of the microdeletions were confirmed to be identical by FISH analysis. We identified highly homologous sequences, i.e., possible low copy repeats (LCRs), in regions flanking proximal and distal. breakpoints of the common deletion. This suggests that LCRs may mediate the deletion. Such LCRs seem to be present in different populations. Thus the different frequency of microdeletions between Japanese and non, Japanese cases in our study may have been caused by patient-selection bias. (C) 2003 Wiley-Liss, Inc.

DOI： 10.1002/humu.10270

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER-VERLAG TOKYO  

Collectins are a family of C-type lectins found in vertebrates. These proteins have four regions, a relatively short N-terminal region, a collagen-like region, an alphahelical coiled coil, and a carbohydrate recognition domain. Collectins are involved in host defense through their ability to bind carbohydrate antigens on microorganisms. Type A scavenger receptors are classical-type scavenger receptors that also have collagen-like domains. We previously described a new scavenger receptor, collectin from placenta [collectin placenta 1 (CL-P1)]. CL-P1 is a type II membrane protein with all four regions. We found that CL-P1 can bind and phagocytize both bacteria and yeast. In addition to that, it reacts with oxidized low-density lipoprotein (LDL) but not with acetylated LDL. These results suggest that CL-P1 might play important roles in host defenses and/or atherosclerosis formation. One rational strategy to study the role of CL-P1 in these pathological conditions would be to perform a haplotype association study using human samples. As a first step for this strategy, we analyzed the haplotype structure of the CL-P1 gene. By sequencing the CL-P1 gene in ten Japanese volunteers, we identified five single-nucleotide polymorphisms (SNPs) with a minor allele frequency of at least 29%. To obtain SNPs in the 5'-upstream region of the gene, we screened a total of 20 SNPs described in the database and finally picked up one SNP for the present study. Thus, a total of six SNPs, one in the 5'-upstream region, two in intron 2, one in exon 5, and two in exon 6, were used to analyze the haplotype structure of the gene, with DNAs derived from 54 individuals (108 alleles). The analysis revealed that only two of six SNPs showed significant linkage disequilibrium (r(2) > 0.5) with each other. This haplotype information may be useful in disease-association studies in which a contribution of the CL-P1 gene has been suspected, especially in immunological disturbance or atherosclerosis. Two SNPs in exon 6, both leading to amino acid substitutions, could be candidates for influencing disease susceptibility.

DOI： 10.1007/s100380300011

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：W B SAUNDERS CO  

Hyperhomocysteinemia, a well-recognized cardiovascular risk factor, is frequent in hemodialysis (HD) patients. A common polymorphism in the 5,10-methyienetetrahydrofolate reductase(MTHFR) gene, C-->T substitution at nucleotide 677, is associated with homocysteine (Hcy) level elevation. We examined whether three factors involved in the methionine cycle could influence plasma Hcy concentrations in HD patients: MTHFR polymorphism; vitamin B-12, an essential cofactor; and folate, the substrate. In a cross-sectional study, serum vitamin B-12, folate, and plasma Hey were measured and MTHFR genotyping was performed in 534 HD patients. Effects of MTHFR genotypes, vitamin 1312, and folate on plasma Hcy levels were examined in 450 HD patients not administered vitamin B-12 or folate. To examine the effect of vitamin B-12 on plasma Hcy concentrations, we compared plasma Hcy concentrations in HD patients with and without vitamin B-12 supplementation. To examine whether functional vitamin B-12 deficiency exists even In HD patients with normal vitamin B-12 concentrations, 15 HD patients (serum vitamin B-12 concentrations, 250 to 2,100 pg/mL) were treated with vitamin B-12 (mecobalamin, 1.5 mg/d) for 8 weeks. Serum concentrations of methylmalonic acid (MMA) and vitamin B-12 were measured. Hcy levels were higher and folate levels were lower in patients with the TT and CT genotypes compared with patients with the CC genotype. Analysis of covariance to determine independent predictors of high Hcy levels identified low serum vitamin B-12 and folate levels and high albumin (Alb) levels in CC-genotype patients, low folate levels and high Alb levels in CT-genotype patients, and low folate levels in TT-genotype patients. Plasma Hcy levels were lower in CC- and CT-genotype patients with vitamin B-12 supplementation than in those without supplementation. Vitamin B-12 supplementation for 8 weeks significantly reduced MMA concentrations in HD patients with normal serum vitamin B-12 concentrations. These results indicate that MTHFR genotype influences the correlation of Hcy level with vitamin B-12 and folate levels in HD patients. Functional vitamin B-12 deficiency may exist, even in HID patients with normal vitamin B-12 concentrations, The efficacy of vitamin 812 and folate supplementation on plasma Hcy levels may depend on MTHFR genotype. (C) 2002 by the National Kidney Foundation, Inc.

DOI： 10.1053/ajkd.2002.32779

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE AMERICA INC  

We isolated NSD1 from the 5q35 breakpoint in an individual with Sotos syndrome harboring a chromosomal translocation. We identified 1 nonsense, 3 frameshift and 20 submicroscopic deletion mutations of NSD1 among 42 individuals with sporadic cases of Sotos syndrome. The results indicate that haploinsufficiency of NSD1 is the major cause of Sotos syndrome.

DOI： 10.1038/ng863

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-LISS  

We recently found mutations of the transforming growth factor beta 1 (TGF-beta1) gene (TGFB1) in 9 families, in which progressive diaphyseal dysplasia (Camurati-Engelmann disease) is segregating [Kinoshita et al., 2000: Nat Genetics 26:19-20]. During the study, we encountered two unrelated girls, aged 17 and 11 years, who had clinical manifestations of the disorder, such as marfanoid habitus, waddling gait, muscular weakness, intense leg pain, flexion contracture of the hip and knee joints, delayed sexual development, increased serum alkaline phosphatase levels, and increased erythrocyte sedimentation rates. Radiographic studies in the two girls demonstrated not only diaphyseal dysplasia (cortical thickening of the diaphyses) resembling that of progressive diaphyseal dysplasia but also metaphyseal expansion of the long bones, coarse and thick trabeculae of the long and short tubular bones, striations in the spinal, pelvic, and long bones, and cranial sclerosis restricted to the petromastoid regions. These radiographic changes were overall identical with those seen in hyperostosis generalisata with striations of the bones rather than those in progressive diaphyseal dysplasia. Polymerase chain reaction-direct sequencing of all exons and their flanking regions of TGFBI did not detect any mutations. PCR-single strand conformational polymorphism analysis of the TGF-beta type 1 receptor gene (TGFBR1) did not demonstrate any aberrant DNA fragments. We concluded from these findings that the two girls we described belong to a unique entity distinct from either of the two disorders. (C) 2001 Wiley-Liss, Inc.

DOI： 10.1002/ajmg.10079

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER-VERLAG TOKYO  

Osteoprotegerin (OPG), a secreted glycoprotein and a member of the tumor necrosis factor receptor superfamily, is considered to play an important role in the regulation of bone resorption by modifying osteoclast differentiation. Overexpression of OPG in mice has been reported to result in osteopetrosis, whereas targeted disruption of OPG in mice has been associated with osteoporosis. Accordingly, OPG could be a strong candidate gene for susceptibility to human osteoporosis. Here, we analyzed whether OPG is involved in the etiology of osteoporosis using both linkage and association analyses. We recruited 164 sib pairs in Gunma prefecture, which is located in the central part of Honshu (mainland Japan), for a linkage study, and 394 postmenopausal women in Akita prefecture, which is in the northern part of Honshu, for an association study. We identified two microsatellite polymorphisms in the linkage study, and six single-nucleotide polymorphisms (SNPs) in the OPG region for the association study. Although, no evidence of significant linkage between OPG and osteoporosis was found, a possible association of one SNP, located in the promoter region of the gene, was identified. A haplotype analysis with the six SNPs revealed that four major haplotypes account for 71% of the alleles in the Japanese population.

DOI： 10.1007/s100380200058

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

A gene for Methyl-CpG binding protein 2 (MECP2), which locates Xq28, was recently found to be responsible for Rett syndrome. Although mutational analyses of MECP2 in Rett syndrome have been extensively analyzed, the mechanism(s) by which variable clinical phenotype occurred between affected monozygotic twins or sisters have not been clarified. We hypothesized that the difference of X-inactivation pattern might explain this phenomenon. With the method, based on methylation-specific PCR, we analyzed polymorphic trinucleotide repeat in the human andorogen receptor gene mapped on Xq11.2-12, using DNA samples derived from previously described monozygotic twins and sisters together with their parents. Their clinical phenotypes were reported to be significantly different between siblings. We found that (1) maternally derived allele is predominantly active than paternally derived one in three out of four patients analyzed, (2) remaining one twin patient, whose ratio of active paternal allele is almost the same level as maternal allele, showed far much severe phenotype when compared with her counterpart. 'Together with the finding that most of the alleles with de novo mutation are from paternal X chromosome in sporadic cases, the existence of a mechanism that suppresses mutated paternal allele activation, resulting skewed X-inactivation to make clinical phenotype milder, might be speculated.. Thus, when this mechanism fails to work sufficiently by an unknown reason, severer clinical phenotype could occur. (C) 2001 Elsevier Science B.V. All rights reserved.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MUNKSGAARD INT PUBL LTD  

Shwachman syndrome is an autosomal-recessive disorder characterized by exocrine pancreatic insufficiency, bone-marrow dysfunction, and metaphyseal chondrodysplasia. A de novo balanced translocation was recently documented in a patient with this disease. Toward isolating the gene(s) responsible for Shwachman syndrome, we cloned and sequenced the translocation breakpoints in the DNA of this patient. The nucleotide sequences around the breakpoints contained neither repetitive elements nor motifs reported to be implicated in recombination events, although we did detect gains or losses of oligonucleotides at the translocation junctions. By large-scale genomic sequencing and in silico gene trapping. we identified two novel transcripts in the vicinity of the breakpoints that might represent candidate genes for Shwachman syndrome, one on chromosome 6 and the other on chromosome 12. The gene on chromosome 12 was actually disrupted by the translocation.

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記述言語：日本語   出版者・発行元：(財)小児愛育協会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The phenotypes of chromosomal 22q11.2 microdeletion are quite variable among individuals and hypoparathyroidism (HP) constitutes a definite portion of the clinical spectrum. For the correct diagnosis and pertinent follow up of the HP children due to del22q11.2, we tried to delineate the clinical characteristics of such patients. By employing fluorescence in situ hybridization (FISH) to all the patients diagnosed as HP in our clinic, ten possessed the 22q11.2 microdeletion. Among them, the incidence of cardiac defect (5/10), recurrent infection (1/10) and cleft palate (1/10) was modest. Additionally, seven of them had been diagnosed as HP during the infantile period, when their facial abnormality and intellectual problem had not become evident. Notably, two patients were complicated by Graves disease, while the association of idiopathic thrombocytopenic purpura was also observed in two girls. Conclusion: HP due to del22q11.2 may be misdiagnosed as idiopathic, especially in an infant who lacks apparent complications like cardiac anomaly. They should be closely followed up for auto-immune complications.

DOI： 10.1007/s004310050762

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Mutations in the gene encoding neural cell adhesion molecule L1 (L1CAM) are involved in X-linked hydrocephalus (HSAS, hydrocephalus due to stenosis of the aqueduct of Sylvius), MASA syndrome (mental retardation, aphasia, shuffling gait, and adducted thumbs), and spastic paraplegia type 1. We examined the L1CAM mutation in a Japanese family with HSAS for the purpose of DNA-based genetic counseling. The proband was a 9-year-old boy who had a 1-bp deletion in exon 22 of the L1CAM gene. This resulted in a shift of the reading frame, and introduction of a premature stop codon. Translation of this mRNA will create a truncated protein without the transmembrane domain, which cannot be expressed on the cell surface. Magnetic resonance images (MRI) revealed markedly enlarged lateral ventricles, hypoplastic white matter, thin cortical mantle, agenesis of the corpus callosum and septum pellucidum, and a fused thalamus. These findings represented impaired L1CAM function during development of the nervous system with resultant adhesion between neurons, neurites outgrowth and fasciculation, and neural cell migration. Screening by Apa I digestion of polymerase chain reaction (PCR) products identified the mother and the younger sister as heterozygous carriers. The carriers were asymptomatic. The father and the other sister did not have the mutation. The identification of L1CAM mutation in families with HSAS will give them the opportunity for DNA-based counseling and prenatal diagnosis. (C) 1997 Elsevier Science B.V.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The girl was the first child of a 29-year-old mother and a 33-years old father. She had soft cleft plate and lower lip pi.ts. The diagnosis of Van der Woude syndrome(VWS) was made. She was first evaluated by us at the age of 3 years because of her short stature. She had postnatal onset growth retardation, typical facial appearance, typical dermatoglyphic pattern, partial growth hormone deficiency and a low normal limit mentality. She was then also diagnosed as having Kabuki make-up syndrome(KMS). The girl was the second case, who represented 2 independent dominant syndromes, KMS and VWS. Recently, gene locus of VWS-1 is assigned at Iq32-41, by microsatellite-based mapping[Sanger et al.,1995]. But her high resolution chromosome failed to show any deletion and aberration on this region.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-LISS  

We report on a 6-year-old girl with SPONASTRIME dysplasia, characterized by short-limbed dwarfism, a relatively large head, midfacial hypoplasia, a saddle nose, moderate deformities of the vertebral bodies, striated metaphyses, and normal intelligence. She showed severe skeletal changes including marked delay of epiphyseal ossification, evident metaphyseal dysplasia, and osteopathia striata more pronounced than in most of the previously reported patients with this disorder. The patient we describe and a male patient reported by Camera et al. [1994: Pediatr Radiol 24:322-324] are likely to represent the severely-affected end of the clinical spectrum of the disorder. These findings thus rule out the X-linked mode of inheritance of the disorder proposed by Camera et al. [1994: Pediatr Radiol 24: 322-324]. Alternatively the two severely-affected patients may represent a variant form of the disorder. There is evidence that SPONASTRIME dysplasia is a genetically heterogeneous disorder. (C) 1996 Wiley-Liss, Inc.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-LISS  

Setleis syndrome is characterized by bitemporal skin depressions resembling forceps marks, abnormalities of the eyelashes, and ''leonine'' facial appearance, The cause is unknown, although autosomal recessive inheritance has been proposed, Recently, two families were reported in which one of the parents of a patient with Setleis syndrome showed mild manifestations, suggesting autosomal dominant inheritance, We describe a 9-month-old Japanese boy with typical Setleis syndrome. His father, who has normal intelligence, has bitemporal focal dermal dysplasia but a normal face. His paternal second cousin also has Setleis syndrome. This family shows autosomal dominant inheritance including father-to-son transmission of Setleis syndrome with variable expressivity and reduced penetrance. Careful examination of the relatives of patients with Setleis syndrome is recommended. (C) 1995 Wiley-Liss, Inc.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-LISS  

We report on a boy with Rieger syndrome, who had an apparently balanced reciprocal translocation between chromosomes 1 and 4, The clinical manifestations of this patient were characterized by irregular shaped pupils with a prominent Schwalbe line and an umbilical hernia, On cytogenetic studies, he was found to have a de novo reciprocal translocation 46,XY,t(1;4) (q23.1;q25), without visible deletion, His parents had normal chromosomes, A review of both cytogenetic and genetic linkage analyses with Rieger syndrome showed that chromosome 4q was involved, This and other previous reports suggested that the gene for Rieger syndrome is mapped to the 4q25-->4q26 segment adjoining the breakpoint. (C) 1995 Wiley-Liss, Inc.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We describe a 22-month-old Japanese girl with severe microcephaly with a prominent nose and a receding chin, developmental delay, marked intrauterine and postnatal dwarfism with limb shortening and brachydactyly, and distinctive radiological changes of the skeleton. The radiological findings include hypoplasia of the short tubular bones, multiple pseudoepiphyses in the bases of the metacarpals, coxa valga, a wide pelvis with iliac flaring, thoracolumbar scoliosis, and disharmonious ossification delay. The clinical and radiological features are somewhat different from those of previously reported cases with osteodysplastic primordial dwarfism. The clinical and radiological manifestations of osteodysplastic primordial dwarfism are reviewed and compared with those in our patient.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-LISS  

In a series of 25 Japanese patients with Rubinstein-Taybi syndrome, we screened, by high-resolution GTG banding and fluorescence in situ hybridization of a cosmid probe (RT1, D16S237), for microdeletions associated with this syndrome. In one patient, a microdeletion was demonstrated by in situ hybridization, but none were detected by high-resolution banding. (C) 1994 Wiley-Liss, Inc.

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記述言語：日本語   著書種別：教科書・概説・概論

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記述言語：日本語   著書種別：教科書・概説・概論

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記述言語：日本語   著書種別：教科書・概説・概論

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記述言語：日本語   著書種別：教科書・概説・概論

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記述言語：日本語   著書種別：一般書・啓蒙書

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総ページ数：xi, 192p   記述言語：日本語  

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記述言語：日本語   著書種別：学術書

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記述言語：日本語   著書種別：学術書

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記述言語：日本語   著書種別：学術書

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記述言語：日本語   著書種別：学術書

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記述言語：日本語   著書種別：学術書

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記述言語：日本語   著書種別：学術書

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記述言語：日本語   著書種別：学術書

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記述言語：日本語   著書種別：学術書

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記述言語：日本語   著書種別：学術書

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記述言語：日本語   著書種別：学術書

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記述言語：日本語   著書種別：学術書

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記述言語：日本語   著書種別：学術書

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記述言語：日本語   著書種別：学術書

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記述言語：日本語   著書種別：学術書

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記述言語：日本語   著書種別：学術書

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記述言語：日本語   著書種別：学術書

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記述言語：日本語   著書種別：学術書

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記述言語：日本語   著書種別：学術書

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記述言語：日本語   著書種別：学術書

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記述言語：日本語   著書種別：学術書

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総ページ数：239p   記述言語：日本語  

CiNii Books

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記述言語：日本語   著書種別：学術書

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記述言語：日本語   著書種別：学術書

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記述言語：日本語   著書種別：学術書

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記述言語：日本語   著書種別：学術書

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記述言語：日本語   著書種別：学術書

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総ページ数：[3] leaves   記述言語：英語  

CiNii Books

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担当区分：責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：日本臨床社  

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担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）   出版者・発行元：北海道医師会  

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記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：日本臨床社  

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担当区分：責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：日本臨床社  

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担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（大学・研究所紀要）   出版者・発行元：旭川医科大学  

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担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：社団法人 日本眼科医会  

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記述言語：日本語  

CiNii Books

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記述言語：日本語  

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記述言語：日本語  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語  

J-GLOBAL

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記述言語：日本語  

J-GLOBAL

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：KARGER  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：KARGER  

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記述言語：日本語   出版者・発行元：日本小児栄養消化器肝臓学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：日本小児栄養消化器肝臓学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：日本遺伝カウンセリング学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：英語   出版者・発行元：ENDOCRINE SOC  

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記述言語：日本語  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：日本語  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：東京医学社  

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/2006126799

記述言語：日本語  

著者版

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その他リンク： http://search.jamas.or.jp/link/ui/2006179611

担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：診断と治療社  

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担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：東京医学社  

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担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：日本臨床社  

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担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：メディカルレビュー社  

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担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：東京医学社  

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担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：東京医学社  

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担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：東京医学社  

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記述言語：日本語  

著者版

CiNii Books

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その他リンク： http://amcor.asahikawa-med.ac.jp/modules/xoonips/detail.php?id=2005258932

記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：メディカル・ドウ  

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記述言語：日本語   出版者・発行元：(一社)日本てんかん学会  

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記述言語：英語  

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/2004307768

記述言語：英語   出版者・発行元：WILEY-LISS  

Sotos syndrome (SoS) is an autosomal dominant overgrowth syndrome with characteristic craniofacial dysmorphic features and various degrees of mental retardation. We previously showed that haploinsufficiency of the NSD1 gene is the major cause of SoS, and submicroscopic deletions at 5q35, including NSD1, were found in about a half (20/42) of our patients examined. Since the first report, an additional 70 SoS cases consisting of 53 Japanese and 17 non-Japanese have been analyzed. We found 50 microdeletions (45%) and 16 point mutations (14%) among all the 112 cases. A large difference in the frequency of microdeletions between Japanese and non Japanese patients was noted: 49 (52%) of the 95 Japanese patients and only one (6%) of the 17 non-Japanese had microdeletions. A sequence-based physical map was constructed to characterize the microdeletions. Most of the microdeletions were confirmed to be identical by FISH analysis. We identified highly homologous sequences, i.e., possible low copy repeats (LCRs), in regions flanking proximal and distal. breakpoints of the common deletion. This suggests that LCRs may mediate the deletion. Such LCRs seem to be present in different populations. Thus the different frequency of microdeletions between Japanese and non, Japanese cases in our study may have been caused by patient-selection bias. (C) 2003 Wiley-Liss, Inc.

DOI： 10.1002/humu.10270

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記述言語：英語   出版者・発行元：BRITISH MED JOURNAL PUBL GROUP  

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記述言語：英語   出版者・発行元：BRITISH MED JOURNAL PUBL GROUP  

DOI： 10.1136/bjo.87.3.367

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記述言語：英語   出版者・発行元：SPRINGER-VERLAG TOKYO  

Collectins are a family of C-type lectins found in vertebrates. These proteins have four regions, a relatively short N-terminal region, a collagen-like region, an alphahelical coiled coil, and a carbohydrate recognition domain. Collectins are involved in host defense through their ability to bind carbohydrate antigens on microorganisms. Type A scavenger receptors are classical-type scavenger receptors that also have collagen-like domains. We previously described a new scavenger receptor, collectin from placenta [collectin placenta 1 (CL-P1)]. CL-P1 is a type II membrane protein with all four regions. We found that CL-P1 can bind and phagocytize both bacteria and yeast. In addition to that, it reacts with oxidized low-density lipoprotein (LDL) but not with acetylated LDL. These results suggest that CL-P1 might play important roles in host defenses and/or atherosclerosis formation. One rational strategy to study the role of CL-P1 in these pathological conditions would be to perform a haplotype association study using human samples. As a first step for this strategy, we analyzed the haplotype structure of the CL-P1 gene. By sequencing the CL-P1 gene in ten Japanese volunteers, we identified five single-nucleotide polymorphisms (SNPs) with a minor allele frequency of at least 29%. To obtain SNPs in the 5'-upstream region of the gene, we screened a total of 20 SNPs described in the database and finally picked up one SNP for the present study. Thus, a total of six SNPs, one in the 5'-upstream region, two in intron 2, one in exon 5, and two in exon 6, were used to analyze the haplotype structure of the gene, with DNAs derived from 54 individuals (108 alleles). The analysis revealed that only two of six SNPs showed significant linkage disequilibrium (r(2) > 0.5) with each other. This haplotype information may be useful in disease-association studies in which a contribution of the CL-P1 gene has been suspected, especially in immunological disturbance or atherosclerosis. Two SNPs in exon 6, both leading to amino acid substitutions, could be candidates for influencing disease susceptibility.

DOI： 10.1007/s100380300011

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J-GLOBAL

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J-GLOBAL

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記述言語：英語   出版者・発行元：W B SAUNDERS CO  

Hyperhomocysteinemia, a well-recognized cardiovascular risk factor, is frequent in hemodialysis (HD) patients. A common polymorphism in the 5,10-methyienetetrahydrofolate reductase(MTHFR) gene, C-->T substitution at nucleotide 677, is associated with homocysteine (Hcy) level elevation. We examined whether three factors involved in the methionine cycle could influence plasma Hcy concentrations in HD patients: MTHFR polymorphism; vitamin B-12, an essential cofactor; and folate, the substrate. In a cross-sectional study, serum vitamin B-12, folate, and plasma Hey were measured and MTHFR genotyping was performed in 534 HD patients. Effects of MTHFR genotypes, vitamin 1312, and folate on plasma Hcy levels were examined in 450 HD patients not administered vitamin B-12 or folate. To examine the effect of vitamin B-12 on plasma Hcy concentrations, we compared plasma Hcy concentrations in HD patients with and without vitamin B-12 supplementation. To examine whether functional vitamin B-12 deficiency exists even In HD patients with normal vitamin B-12 concentrations, 15 HD patients (serum vitamin B-12 concentrations, 250 to 2,100 pg/mL) were treated with vitamin B-12 (mecobalamin, 1.5 mg/d) for 8 weeks. Serum concentrations of methylmalonic acid (MMA) and vitamin B-12 were measured. Hcy levels were higher and folate levels were lower in patients with the TT and CT genotypes compared with patients with the CC genotype. Analysis of covariance to determine independent predictors of high Hcy levels identified low serum vitamin B-12 and folate levels and high albumin (Alb) levels in CC-genotype patients, low folate levels and high Alb levels in CT-genotype patients, and low folate levels in TT-genotype patients. Plasma Hcy levels were lower in CC- and CT-genotype patients with vitamin B-12 supplementation than in those without supplementation. Vitamin B-12 supplementation for 8 weeks significantly reduced MMA concentrations in HD patients with normal serum vitamin B-12 concentrations. These results indicate that MTHFR genotype influences the correlation of Hcy level with vitamin B-12 and folate levels in HD patients. Functional vitamin B-12 deficiency may exist, even in HID patients with normal vitamin B-12 concentrations, The efficacy of vitamin 812 and folate supplementation on plasma Hcy levels may depend on MTHFR genotype. (C) 2002 by the National Kidney Foundation, Inc.

DOI： 10.1053/ajkd.2002.32779

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記述言語：英語   出版者・発行元：W B SAUNDERS CO  

Hyperhomocysteinemia, a well-recognized cardiovascular risk factor, is frequent in hemodialysis (HD) patients. A common polymorphism in the 5,10-methyienetetrahydrofolate reductase(MTHFR) gene, C-->T substitution at nucleotide 677, is associated with homocysteine (Hcy) level elevation. We examined whether three factors involved in the methionine cycle could influence plasma Hcy concentrations in HD patients: MTHFR polymorphism; vitamin B-12, an essential cofactor; and folate, the substrate. In a cross-sectional study, serum vitamin B-12, folate, and plasma Hey were measured and MTHFR genotyping was performed in 534 HD patients. Effects of MTHFR genotypes, vitamin 1312, and folate on plasma Hcy levels were examined in 450 HD patients not administered vitamin B-12 or folate. To examine the effect of vitamin B-12 on plasma Hcy concentrations, we compared plasma Hcy concentrations in HD patients with and without vitamin B-12 supplementation. To examine whether functional vitamin B-12 deficiency exists even In HD patients with normal vitamin B-12 concentrations, 15 HD patients (serum vitamin B-12 concentrations, 250 to 2,100 pg/mL) were treated with vitamin B-12 (mecobalamin, 1.5 mg/d) for 8 weeks. Serum concentrations of methylmalonic acid (MMA) and vitamin B-12 were measured. Hcy levels were higher and folate levels were lower in patients with the TT and CT genotypes compared with patients with the CC genotype. Analysis of covariance to determine independent predictors of high Hcy levels identified low serum vitamin B-12 and folate levels and high albumin (Alb) levels in CC-genotype patients, low folate levels and high Alb levels in CT-genotype patients, and low folate levels in TT-genotype patients. Plasma Hcy levels were lower in CC- and CT-genotype patients with vitamin B-12 supplementation than in those without supplementation. Vitamin B-12 supplementation for 8 weeks significantly reduced MMA concentrations in HD patients with normal serum vitamin B-12 concentrations. These results indicate that MTHFR genotype influences the correlation of Hcy level with vitamin B-12 and folate levels in HD patients. Functional vitamin B-12 deficiency may exist, even in HID patients with normal vitamin B-12 concentrations, The efficacy of vitamin 812 and folate supplementation on plasma Hcy levels may depend on MTHFR genotype. (C) 2002 by the National Kidney Foundation, Inc.

DOI： 10.1053/ajkd.2002.32779

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記述言語：英語   出版者・発行元：NATURE AMERICA INC  

We isolated NSD1 from the 5q35 breakpoint in an individual with Sotos syndrome harboring a chromosomal translocation. We identified 1 nonsense, 3 frameshift and 20 submicroscopic deletion mutations of NSD1 among 42 individuals with sporadic cases of Sotos syndrome. The results indicate that haploinsufficiency of NSD1 is the major cause of Sotos syndrome.

DOI： 10.1038/ng863

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記述言語：英語   出版者・発行元：WILEY-LISS  

We recently found mutations of the transforming growth factor beta 1 (TGF-beta1) gene (TGFB1) in 9 families, in which progressive diaphyseal dysplasia (Camurati-Engelmann disease) is segregating [Kinoshita et al., 2000: Nat Genetics 26:19-20]. During the study, we encountered two unrelated girls, aged 17 and 11 years, who had clinical manifestations of the disorder, such as marfanoid habitus, waddling gait, muscular weakness, intense leg pain, flexion contracture of the hip and knee joints, delayed sexual development, increased serum alkaline phosphatase levels, and increased erythrocyte sedimentation rates. Radiographic studies in the two girls demonstrated not only diaphyseal dysplasia (cortical thickening of the diaphyses) resembling that of progressive diaphyseal dysplasia but also metaphyseal expansion of the long bones, coarse and thick trabeculae of the long and short tubular bones, striations in the spinal, pelvic, and long bones, and cranial sclerosis restricted to the petromastoid regions. These radiographic changes were overall identical with those seen in hyperostosis generalisata with striations of the bones rather than those in progressive diaphyseal dysplasia. Polymerase chain reaction-direct sequencing of all exons and their flanking regions of TGFBI did not detect any mutations. PCR-single strand conformational polymorphism analysis of the TGF-beta type 1 receptor gene (TGFBR1) did not demonstrate any aberrant DNA fragments. We concluded from these findings that the two girls we described belong to a unique entity distinct from either of the two disorders. (C) 2001 Wiley-Liss, Inc.

DOI： 10.1002/ajmg.10079

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記述言語：英語   出版者・発行元：SPRINGER-VERLAG TOKYO  

Osteoprotegerin (OPG), a secreted glycoprotein and a member of the tumor necrosis factor receptor superfamily, is considered to play an important role in the regulation of bone resorption by modifying osteoclast differentiation. Overexpression of OPG in mice has been reported to result in osteopetrosis, whereas targeted disruption of OPG in mice has been associated with osteoporosis. Accordingly, OPG could be a strong candidate gene for susceptibility to human osteoporosis. Here, we analyzed whether OPG is involved in the etiology of osteoporosis using both linkage and association analyses. We recruited 164 sib pairs in Gunma prefecture, which is located in the central part of Honshu (mainland Japan), for a linkage study, and 394 postmenopausal women in Akita prefecture, which is in the northern part of Honshu, for an association study. We identified two microsatellite polymorphisms in the linkage study, and six single-nucleotide polymorphisms (SNPs) in the OPG region for the association study. Although, no evidence of significant linkage between OPG and osteoporosis was found, a possible association of one SNP, located in the promoter region of the gene, was identified. A haplotype analysis with the six SNPs revealed that four major haplotypes account for 71% of the alleles in the Japanese population.

DOI： 10.1007/s100380200058

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記述言語：英語   出版者・発行元：SPRINGER-VERLAG TOKYO  

Osteoprotegerin (OPG), a secreted glycoprotein and a member of the tumor necrosis factor receptor superfamily, is considered to play an important role in the regulation of bone resorption by modifying osteoclast differentiation. Overexpression of OPG in mice has been reported to result in osteopetrosis, whereas targeted disruption of OPG in mice has been associated with osteoporosis. Accordingly, OPG could be a strong candidate gene for susceptibility to human osteoporosis. Here, we analyzed whether OPG is involved in the etiology of osteoporosis using both linkage and association analyses. We recruited 164 sib pairs in Gunma prefecture, which is located in the central part of Honshu (mainland Japan), for a linkage study, and 394 postmenopausal women in Akita prefecture, which is in the northern part of Honshu, for an association study. We identified two microsatellite polymorphisms in the linkage study, and six single-nucleotide polymorphisms (SNPs) in the OPG region for the association study. Although, no evidence of significant linkage between OPG and osteoporosis was found, a possible association of one SNP, located in the promoter region of the gene, was identified. A haplotype analysis with the six SNPs revealed that four major haplotypes account for 71% of the alleles in the Japanese population.

DOI： 10.1007/s100380200058

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記述言語：日本語  

CiNii Books

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記述言語：日本語  

CiNii Books

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記述言語：日本語  

CiNii Books

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記述言語：日本語   出版者・発行元：日本先天代謝異常学会  

CiNii Books

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：UNIV CHICAGO PRESS  

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記述言語：日本語  

CiNii Books

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記述言語：英語   出版者・発行元：OXFORD UNIV PRESS  

Transient neonatal diabetes mellitus (TNDM) is associated with intra-uterine growth retardation, dehydration and a lack of insulin. Some TNDM patients exhibit paternal uniparental disomy (UPD) of chromosome 6q24, where at least two imprinted genes, HYMAI and ZAC, have so far been characterized. Here we show that the differentially methylated CpG island that partially overlaps mZac1 and mHymai at the syntenic mouse locus is a likely imprinting control region (ICR) for the similar to 120-200 kb domain. The region is unmethylated in sperm but probably methylated in oocytes, a difference that persists between parental alleles throughout pre- and post-implantation development. We also show that within this ICR, there is a region that exhibits a high degree of homology between mouse and human. Using a reporter expression assay, we demonstrate that this conserved region acts as a strong transcriptional repressor when methylated. Finally, we provide in vivo evidence that in the majority of TNDM patients with a normal karyotype, there is a loss of methylation within the highly homologous region. We propose that this ICR regulates expression of imprinted genes within the domain; epigenetic or genetic mutations of this region probably result in TNDM, possibly by affecting expression of ZAC in the pancreas and/or the pituitary.

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記述言語：英語   出版者・発行元：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Transforming growth factor (TGF)-beta1 is secreted as a latent form, which consists of its mature form and a latency-associated peptide (beta1-LAP) in either the presence or the absence of additional latent TGF-beta1-binding protein. We recently reported that three different missense mutations (R218H, R218C, and C225R) of beta1-LAP cause the Camurati-Engelmann disease (CED), an autosomal dominant disorder characterized by hyperosteosis and sclerosis of the diaphysis of the long bones. Pulse-chase experiments using fibroblasts from CED patients and expression experiments of the mutant genes in an insect cell system suggest that these mutations disrupt the association of beta1-LAP and TGF-beta1 and the subsequent release of the mature TGF-beta1. Furthermore, the cell growth of fibroblasts from a CED patient and mutant gene-transfected fibroblasts was suppressed via TGF-beta1. The growth suppression observed was attenuated by neutralizing antibody to TFF-beta1 or by treatment of dexamethasone. On the other hand, the proliferation of human osteoblastic MG-63 cells was accelerated by coculture with CED fibroblasts. These data suggest that the domain-specific mutations of beta1-LAP result in a more facile activation of TGF-beta1, thus causing CED.

DOI： 10.1074/jbc.C000859200

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PubMed

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J-GLOBAL

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記述言語：日本語   掲載種別：速報，短報，研究ノート等（学術雑誌）   出版者・発行元：(公社)日本整形外科学会  

J-GLOBAL

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：UNIV CHICAGO PRESS  

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記述言語：英語   出版者・発行元：NATURE AMERICA INC  

DOI： 10.1038/79128

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PubMed

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記述言語：英語   出版者・発行元：WILEY-LISS  

We report on clinical and radiologic manifestations in a 3 -generation Japanese family with Engelmann disease (ED) or progressive diaphyseal dysplasia, A large variation of phenotype was remarkable among 12 affected family members. Of the 12 patients, 7 had full manifestations of ED, such as bilateral, symmetrical diaphyseal sclerosis of long bones with myopathy and limb pain, whereas the other 5 exhibited only segmental (rhizomelic and/or mesomelic) involvement and asymmetric diaphyseal sclerosis without any clinical symptoms. The phenotype of the latter group of patients resembled Ribbing disease (RD). We propose that ED and RD represent phenotypic variation of the same disorder. (C) 2000 Wiley-Liss, Inc.

DOI： 10.1002/(SICI)1096-8628(20000313)91:2<153::AID-AJMG15>3.0.CO;2-U

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記述言語：英語   出版者・発行元：UNIV CHICAGO PRESS  

Camurati-Engelmann disease (CED [MIM 131300]), or progressive diaphyseal dysplasia, is an autosomal dominant sclerosing bone dysplasia characterized by progressive bone formation along the periosteal and endosteal surfaces at the diaphyseal and metaphyseal regions of long bones and cranial hyperostosis, particularly at the skull base. The gene for CED, or its chromosomal localization, has not yet been identified. We performed a genomewide linkage analysis of two unrelated Japanese families with CED, in which a total of 27 members were available for this study; 16 of them were affected with the disease. Two-point linkage analysis revealed a maximum LOD score of 7.41 (recombination fraction .00; penetrance 1.00) for the D19S918 microsatellite marker locus. Haplotype analysis revealed that all the affected individuals shared a common haplotype observed, in each family, between D19S881 and D19S606, at chromosome 19q13.1-q13.3. These findings, together with a genetic distance among the marker loci, indicate that the CED locus can be assigned to a 15.1-cM segment between D19S881 and D19S606.

DOI： 10.1086/302728

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記述言語：英語   出版者・発行元：WILEY-LISS  

We reported on a B-year-old Japanese girl with clinical manifestations of Kabuki make-up syndrome (KMS) and van der Woude syndrome (VWS), Since the concurrence of the two syndromes is known in four patients, including ours, it suggests a common cause. Assuming that the association of the two syndromes was caused by a microdeletion: involving the putative KMS/VWS genes, we carried out fluorescence in situ hybridization and microsatellite analyses using PAC clones and dinucleotide repeat markers spanning the VWS1 critical region at 1q32-q41, No deletion was detected at the VWS1 critical region. (C) 1999 Wiley-Liss, Inc.

DOI： 10.1002/(SICI)1096-8628(19990917)86:3<285::AID-AJMG18>3.0.CO;2-E

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記述言語：英語   掲載種別：速報，短報，研究ノート等（学術雑誌）   出版者・発行元：UNIV CHICAGO PRESS  

Web of Science

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記述言語：英語   掲載種別：記事・総説・解説・論説等（学術雑誌）   出版者・発行元：WILEY-LISS  

We describe a further patient with the Coffin-Siris syndrome who presented at 4 months with recurrent hypoglycemia attacks. Detailed examination was undertaken at 7 months but the cause of hypoglycemia was not detected. Hypoglycemia seems to be a previously undescribed finding in the Coffin-Siris syndrome. (C) 1995 Wiley-Liss, Inc.

Web of Science

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記述言語：英語   掲載種別：速報，短報，研究ノート等（学術雑誌）   出版者・発行元：WILEY-LISS  

Web of Science

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記述言語：英語   掲載種別：記事・総説・解説・論説等（学術雑誌）   出版者・発行元：MUNKSGAARD INT PUBL LTD  

A 5-year-old boy, who had pre- and postnatal growth retardation, delayed motor development, cutis laxa, delayed closure of large fontanels, congenital hip dislocation and characteristic facies, is described. Disorders with cutis laxa are now divided into five types. The patient had clinical manifestations very similar to those of cutis laxa with bone dystrophy (type II autosomal recessive cutis laxa). Eighteen patients have been reported, the ratio of males to females being 5 to 14. This is the fifth case of this disorder occurring in a male, which provides further evidence for autosomal recessive inheritance.

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：UNIV CHICAGO PRESS  

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