研究者詳細 - 石浦　浩之

Dominant Mutations in RP1L1 Are Responsible for Occult Macular Dystrophy 査読

Masakazu Akahori, Kazushige Tsunoda, Yozo Miyake, Yoko Fukuda, Hiroyuki Ishiura, Shoji Tsuji, Tomoaki Usui, Tetsuhisa Hatase, Makoto Nakamura, Hisao Ohde, Takeshi Itabashi, Haru Okamoto, Yuichiro Takada, Takeshi Iwata

AMERICAN JOURNAL OF HUMAN GENETICS 87 ( 3 ) 424 - 429 2010年9月

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

Occult macular dystrophy (OMD) is an inherited macular dystrophy characterized by progressive loss of macular function but normal ophthalmoscopic appearance. Typical OMD is characterized by a central cone dysfunction leading to a loss of vision despite normal ophthalmoscopic appearance, normal fluorescein angiography, and normal full-field electroretinogram (ERGs), but the amplitudes of the focal macular ERGs and multifocal ERGs are significantly reduced at the central retina. Linkage analysis of two OMD families was performed by the SNP High Throughput Linkage analysis system (SNP HiTLink), localizing the disease locus to chromosome 8p22-p23. Among the 128 genes in the linkage region, 22 genes were expressed in the retina, and four candidate genes were selected. No mutations were found in the first three candidate genes, methionine sulfoxide reductase A (MSRA), GATA binding 4 (GATA4), and pericentriolar material 1 (PCM1). However, amino acid substitution of p.Arg45Trp in retinitis pigmentosa 1-like 1 (RP1L1) was found in three OMD families and p.Trp960Arg in a remaining OMD family. These two mutations were detected in all affected individuals but in none of the 876 controls. Immunohistochemistry of RP1L1 in the retina section of cynomolgus monkey revealed expression in the rod and cone photoreceptor, supporting a role of RP1L1 in the photoreceptors that, when disrupted by mutation, leads to OMD. Identification of RP1L1 mutations as causative for OMD has potentially broader implications for understanding the differential cone photoreceptor functions in the fovea and the peripheral retina.

DOI： 10.1016/j.ajhg.2010.08.009

Multiplexed resequencing analysis to identify rare variants in pooled DNA with barcode indexing using next-generation sequencer 査読

Jun Mitsui, Yoko Fukuda, Kyo Azuma, Hirokazu Tozaki, Hiroyuki Ishiura, Yuji Takahashi, Jun Goto, Shoji Tsuji

JOURNAL OF HUMAN GENETICS 55 ( 7 ) 448 - 455 2010年7月

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

We have recently found that multiple rare variants of the glucocerebrosidase gene (GBA) confer a robust risk for Parkinson disease, supporting the 'common disease-multiple rare variants' hypothesis. To develop an efficient method of identifying rare variants in a large number of samples, we applied multiplexed resequencing using a next-generation sequencer to identification of rare variants of GBA. Sixteen sets of pooled DNAs from six pooled DNA samples were prepared. Each set of pooled DNAs was subjected to polymerase chain reaction to amplify the target gene (GBA) covering 6.5 kb, pooled into one tube with barcode indexing, and then subjected to extensive sequence analysis using the SOLiD System. Individual samples were also subjected to direct nucleotide sequence analysis. With the optimization of data processing, we were able to extract all the variants from 96 samples with acceptable rates of false-positive single-nucleotide variants. Journal of Human Genetics (2010) 55, 448-455; doi:10.1038/jhg.2010.46; published online 20 May 2010

DOI： 10.1038/jhg.2010.46

A Case of Atypical Amyloid Polyneuropathy with Predominant Upper-limb Involvement with the Diagnosis Unexpectedly Found at Lung Operation 査読

Yuichiro Shirota, Atsushi Iwata, Hiroyuki Ishiura, Meiko Hashimoto, Jun Goto, Jun Shimizu, Ritsuko Hanajima, Jun Nakajima, Yutaka Takazawa, Shoji Tsuji

INTERNAL MEDICINE 49 ( 15 ) 1627 - 1631 2010年

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 SOC INTERNAL MEDICINE

We present a patient of familial amyloid polyneuropathy (FAP) with predominant upper-limb involvement, the pattern of which resembled a mononeuropathy multiplex pattern. Sural nerve biopsy failed to diagnose the disorder, but lung partial resection performed later for other diagnostic purposes suggested FAP. A rare mutation in the transthyretin gene (S50R) was subsequently confirmed. Diagnostic challenges of FAP with atypical clinical presentations, including difficulties in pathological diagnosis, are discussed with a review of the literature.

DOI： 10.2169/internalmedicine.49.3663

SNP Haplotype Mapping in a Small ALS Family 査読

Katherine A. Dick Krueger, Shoji Tsuji, Yoko Fukuda, Yuji Takahashi, Jun Goto, Jun Mitsui, Hiroyuki Ishiura, Joline C. Dalton, Michael B. Miller, John W. Day, Laura P. W. Ranum

PLOS ONE 4 ( 5 ) e5687 2009年5月

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

The identification of genes for monogenic disorders has proven to be highly effective for understanding disease mechanisms, pathways and gene function in humans. Nevertheless, while thousands of Mendelian disorders have not yet been mapped there has been a trend away from studying single-gene disorders. In part, this is due to the fact that many of the remaining single-gene families are not large enough to map the disease locus to a single site in the genome. New tools and approaches are needed to allow researchers to effectively tap into this genetic gold-mine. Towards this goal, we have used haploid cell lines to experimentally validate the use of high-density single nucleotide polymorphism (SNP) arrays to define genome-wide haplotypes and candidate regions, using a small amyotrophic lateral sclerosis (ALS) family as a prototype. Specifically, we used haploid-cell lines to determine if high-density SNP arrays accurately predict haplotypes across entire chromosomes and show that haplotype information significantly enhances the genetic information in small families. Panels of haploid-cell lines were generated and a 5 centimorgan (cM) short tandem repeat polymorphism (STRP) genome scan was performed. Experimentally derived haplotypes for entire chromosomes were used to directly identify regions of the genome identical-by-descent in 5 affected individuals. Comparisons between experimentally determined and in silico haplotypes predicted from SNP arrays demonstrate that SNP analysis of diploid DNA accurately predicted chromosomal haplotypes. These methods precisely identified 12 candidate intervals, which are shared by all 5 affected individuals. Our study illustrates how genetic information can be maximized using readily available tools as a first step in mapping single-gene disorders in small families.

DOI： 10.1371/journal.pone.0005687