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Dai J.,RIKEN | Dai J.,Nanjing University | Cho T.-J.,Seoul National University | Unger S.,Albert Ludwigs University of Freiburg | And 5 more authors.
Journal of Human Genetics | Year: 2010

Transient receptor potential cation channel, subfamily V, member 4 (TRPV4) is a calcium-permeable nonselective cation channel of unknown biological function. TRPV4 mutation was first identified in brachyolmia, and then in a spectrum of autosomal-dominant skeletal dysplasias, which includes Kozlowski type of spondylometaphyseal dysplasia, metatropic dysplasia, Maroteaux type of spondyloepiphyseal dysplasia and parastremmatic dysplasia. Recently, TRPV4 mutation has also been identified in a spectrum of neuromuscular diseases that includes congenital distal spinal muscular atrophy (SMA), scapuloperoneal SMA, and hereditary motor and sensory neuropathy type IIC. These diverse spectrums of diseases compose a novel channelopathy, TRPV4-pathy, which could further include polygenic traits such as serum sodium concentration and a chronic obstructive pulmonary disease. In this review, we clarified the TRPV4 mutation spectrum, and discussed the phenotypic complexity of TRPV4-pathy and its pathogenic mechanisms. TRPV4-pathy may extend further to other monogenic and polygenic diseases. © 2010 The Japan Society of Human Genetics All rights reserved.

Miyake N.,Yokohama City University | Kosho T.,Shinshu University | Mizumoto S.,Hokkaido University | Furuichi T.,RIKEN | And 21 more authors.
Human Mutation | Year: 2010

Ehlers-Danlos syndrome (EDS) is a heterogeneous connective tissue disorder involving skin and joint laxity and tissue fragility. A new type of EDS, similar to kyphoscoliosis type but without lysyl hydroxylase deficiency, has been investigated. We have identified a homozygous CHST14 (carbohydrate sulfotransferase 14) mutation in the two familial cases and compound heterozygous mutations in four sporadic cases. CHST14 encodes dermatan 4-O-sulfotransferase 1 (D4ST1), which transfers active sulfate from 3′-phosphoadenosine 5′-phosphosulfate to position 4 of the N-acetyl-Dgalactosamine (GalNAc) residues of dermatan sulfate (DS). Transfection experiments of mutants and enzyme assays using fibroblast lysates of patients showed the loss of D4ST1 activity. CHST14 mutations altered the glycosaminoglycan (GAG) components in patients' fibroblasts. Interestingly, DS of decorin proteoglycan, a key regulator of collagen fibril assembly, was completely lost and replaced by chondroitin sulfate (CS) in the patients' fibroblasts, leading to decreased flexibility of GAG chains. The loss of the decorin DS proteoglycan due to CHST14 mutations may preclude proper collagen bundle formation or maintenance of collagen bundles while the sizes and shapes of collagen fibrils are unchanged as observed in the patients' dermal tissues. These findings indicate the important role of decorin DS in the extracellular matrix and a novel pathomechanism in EDS. © 2010 Wiley-Liss, Inc.

Unger S.,University of Lausanne | Gorna M.W.,Austrian Academy of Sciences | Le Bechec A.,Swiss Institute of Bioinformatics | Do Vale-Pereira S.,University of Lausanne | And 20 more authors.
American Journal of Human Genetics | Year: 2013

Kenny-Caffey syndrome (KCS) and the similar but more severe osteocraniostenosis (OCS) are genetic conditions characterized by impaired skeletal development with small and dense bones, short stature, and primary hypoparathyroidism with hypocalcemia. We studied five individuals with KCS and five with OCS and found that all of them had heterozygous mutations in FAM111A. One mutation was identified in four unrelated individuals with KCS, and another one was identified in two unrelated individuals with OCS; all occurred de novo. Thus, OCS and KCS are allelic disorders of different severity. FAM111A codes for a 611 amino acid protein with homology to trypsin-like peptidases. Although FAM111A has been found to bind to the large T-antigen of SV40 and restrict viral replication, its native function is unknown. Molecular modeling of FAM111A shows that residues affected by KCS and OCS mutations do not map close to the active site but are clustered on a segment of the protein and are at, or close to, its outer surface, suggesting that the pathogenesis involves the interaction with as yet unidentified partner proteins rather than impaired catalysis. FAM111A appears to be crucial to a pathway that governs parathyroid hormone production, calcium homeostasis, and skeletal development and growth. © 2013 The American Society of Human Genetics.

Ichino M.,Health Science University | Kusaka M.,Health Science University | Kuroyanagi Y.,Health Science University | Mori T.,Health Science University | And 6 more authors.
Journal of Urology | Year: 2010

Purpose: Renal scarring is a serious complication that often occurs with chronic pyelonephritis in the presence of vesicoureteral reflux. In a previous study we established a rat model of renal scarring in which we found the up-regulation of neutrophil-gelatinase associated lipocalin at the mRNA and protein levels. In this study we evaluated urinary neutrophil-gelatinase associated lipocalin as a potential biomarker for progression of renal scarring in patients with vesicoureteral reflux. Materials and Methods: A total of 34 patients diagnosed with vesicoureteral reflux without evidence of current urinary tract infection and 28 normal healthy children were enrolled in this study. Renal scars were evaluated by 99mtechnetium dimercapto-succinic acid renal scan in 24 of the reflux cases. Urinary neutrophil-gelatinase associated lipocalin levels were monitored by ELISA. Results: In normal subjects urinary neutrophil-gelatinase associated lipocalin was high during infancy, decreased rapidly within the following year and reached a low stable level from age 3 years onward. Urinary neutrophil-gelatinase associated lipocalin levels, normalized to age matched standards, were significantly increased in patients with vesicoureteral reflux compared to controls. These levels did not correlate with reflux grade, but were significantly higher in patients with radiological evidence of renal scarring irrespective of reflux grade. Conclusions: Estimation of urinary neutrophil-gelatinase associated lipocalin may be useful as a noninvasive diagnostic or prognostic biomarker for renal scarring. © 2010 American Urological Association Education and Research, Inc.

Cho T.-J.,Seoul National University | Kim O.-H.,Ajou University | Choi I.H.,Seoul National University | Nishimura G.,Tokyo Metropolitan Kiyose Childrens Hospital | And 4 more authors.
Journal of Medical Genetics | Year: 2010

A three-generation family with four patients affected by a novel mesomelic dysplasia was investigated for genome-wide DNA copy number variation profiles. This revealed a microduplication of a 1.0-Mb chromosomal segment at 2q31.1 spanning nine Homeo box D (HOXD) genes that co-segregated with the phenotype. Quantitative PCR analysis of a gene within this duplicated region showed consistent results. Mesomelic dysplasia Kantaputra type (MDK; MIM 156232),which shares some phenotypes with this family, has also been mapped to a chromosomal region comprising 2q31.1, raising the possibility that MDK and the condition observed in this family may be allelic.

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