Oyazato Y.,Kobe University |
Iijima K.,Kobe University |
Emi M.,DNA Chip Research Institute |
Sekine T.,Toho University |
And 6 more authors.
Kobe Journal of Medical Sciences | Year: 2011
Background: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in either of two genes, TSC1 and TSC2. Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2. TSC2 lies immediately adjacent to PKD1 and large heterozygous deletions can result in the TSC2/PKD1 contiguous gene syndrome (PKDTS). PKDTS has been identified in patients with TSC and early-onset severe ADPKD. However, genetic diagnosis with conventional methods proved to be difficult because its genetic aberrations are large monoallelic mutations. Methods: In the study presented here, we used both multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (array-CGH) for four PKDTS patients. Results: We were able to detect large heterozygous deletions including TSC2 and PKD1 by both of MLPA and array-CGH in all four patients. And in two patients, array-CGH identified relatively large genomic aberrations (RAB26, NTHL1, etc.), that extended outside of TSC2 or PKD1. Conclusion: The identical results obtained with these two completely different methods show that both constitute highly reliable strategies. Only a few studies have determined the breakpoints of large deletions in this disease and ours is the first to have identified the breakpoints by using array-CGH. We suggest that these methods are not only useful for the diagnosis of PKDTS but also for elucidation of its molecular mechanism. Source
Sekimoto T.,University of Miyazaki |
Ishii M.,DNA Chip Research Institute |
Emi M.,University of Hawaii at Manoa |
Kurogi S.,University of Miyazaki |
And 3 more authors.
Journal of Orthopaedic Research | Year: 2013
Acetabular dysplasia (AD) appears to be a multi-factorial disease, which may involve both genetic and environmental factors and whose pathogenesis remains obscure. The present study aims to identify a genetic variation that might confer risk of AD. We performed whole-genome screening of a copy number variation (CNV) using a deCODE-Illumina CNV beadchip with 20 female AD patients and 131 control subjects. Subsequently, Agilent's region-targeted high-density oligonucleotide tiling microarray was used to analyze 64 female AD patients and 32 female control subjects. By sequential analyses, we found a copy number loss in 18 of 64 AD patients, but none in the 32 controls. The loss occurred within a 472 kb region on 9q22.2, which harbors the gene for Semaphorin 4D (Sema4D; 18/64 vs. 0/32, p = 4.81 × 10-4, OR = 25.86). We suggest that a copy number loss of the Sema4D gene region may play a role in the etiology of AD. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. Source
Yanagimachi M.,Yokohama City University |
Naruto T.,Yokohama City University |
Miyamae T.,Yokohama City University |
Hara T.,Yokohama City University |
And 7 more authors.
Journal of Rheumatology | Year: 2011
Objective. Systemic-onset juvenile idiopathic arthritis (systemic JIA) and macrophage activation syndrome (MAS), the most devastating complication of systemic JIA, are characterized by abnormal levels of proinflammatory cytokines. Interferon regulatory factor 5 (IRF5) is a member of the IRF family of transcription factors, and acts as a master transcription factor in the activation of genes encoding proinflammatory cytokines. Polymorphisms in the IRF5 gene have been associated with susceptibility to autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis. Our aim was to assess associations of IRF5 gene polymorphisms with susceptibility to systemic JIA and MAS. Methods. Three IRF5 single-nucleotide polymorphisms (rs729302, rs2004640, and rs2280714) were genotyped using TaqMan assays in 81 patients with systemic JIA (33 with MAS, 48 without) and 190 controls. Results. There were no associations of the IRF5 gene polymorphisms or haplotypes under study with susceptibility to systemic JIA. There was a significant association of the rs2004640 T allele with MAS susceptibility (OR 4.11; 95% CI 1.84, 9.16; p = 0.001). The IRF5 haplotype (rs729302 A, rs2004640 T, and rs2280714 T), which was reported as conferring an increased risk of SLE, was significantly associated with MAS susceptibility in patients with systemic JIA (OR 4.61; 95% CI 1.73, 12.3; p < 0.001). Conclusion. IRF5 gene polymorphism is a genetic factor influencing susceptibility to MAS in patients with systemic JIA, and IRF5 contributes to the pathogenesis of MAS in these patients. The Journal of Rheumatology Copyright © 2011. All rights reserved. Source
Nakayama M.,National Center for Child Health and Development |
Nakayama M.,Tohoku University |
Nozu K.,Kobe University |
Goto Y.,National Center for Child Health and Development |
And 8 more authors.
Pediatric Nephrology | Year: 2010
Hepatocyte nuclear factor 1β (HNF1β) abnormalities have been recognized to cause congenital anomalies of the kidney and urinary tract (CAKUT), predominantly affecting bilateral renal malformations. To further understand the spectrum of HNF1β related phenotypes, we performed HNF1B gene mutation and deletion analyses in Japanese patients with renal hypodysplasia (n=31), unilateral multicystic dysplastic kidney (MCDK; n=14) and others (n=5). We identified HNF1B alterations in 5 out of 50 patients (10%). De novo heterozygous complete deletions of HNF1B were found in 3 patients with unilateral MCDK. Two of the patients showed contralateral hypodysplasia, whereas the other patient showed a radiologically normal contralateral kidney with normal renal function. Copy number variation analyses showed 1.4 Mb microdeletions involving the whole HNF1B gene with breakpoints in flanking segmental duplications. We also identified 1 novel truncated mutation (1007insC) and another missense mutation (226G>T) in patients with bilateral hypodysplasia. HNF1B alterations leading to haploinsufficiency affect a diverse spectrum of CAKUT. The existence of a patient with unilateral MCDK with normal renal function might provide genetic insight into the etiology of these substantial populations of only unilateral MCDK. The recurrent microdeletions encompassing HNF1B could have a significant impact on the mechanism of HNF1B deletions. © 2010 IPNA. Source
Kato T.,Yamagata University |
Sato H.,Yamagata University |
Sato H.,DNA Chip Research Institute |
Emi M.,Yamagata University |
And 7 more authors.
Internal Medicine | Year: 2011
Objective Idiopathic normal pressure hydrocephalus (iNPH) is clinically important as a treatable gait disturbance or preventable dementia by shunt operation. We have recently reported that approximately 1.5% of the elderly living in a Japanese community showed ventriculomegaly with features of iNPH on MRI (VIM), which may represent a preclinical stage of iNPH. The purpose of the present study was to identify a possible genetic change in VIM subjects. Methods Eight subjects with VIM and 10 healthy individuals were examined for copy number variations (CNV) with a CNV-targeted whole-genome oligonucleotide microarray (Agilent 400 K CNV array). Another panel of 100 healthy Japanese individuals was screened for CNV by whole-genome using the deCODE-Illumina CNV 370 K chip. Immunohistochemical examination of the human brain was performed using an avidin-biotin-peroxidase complex method. Results Among several genetic changes observed, a copy number loss within the SFMBT1 gene was seen in half of the VIM cases (4 of 8 cases), that was rare among the Japanese control subjects (0/10 by Agilent 400 K CNV array or 1/100 by deCODE/Illumina CNV 370 K chip). Immunohistochemical examination of the human brain revealed that the SFMBT1 protein was localized mainly in the arterial walls, the ependymal cells, and the epithelium of the choroid plexus, all of which play a crucial role in the CSF circulation. Conclusion A segmental copy number loss of the SFMBT1 gene may be involved in the pathological process in some individuals with VIM/iNPH. © 2011 The Japanese Society of Internal Medicine. Source