IR@PKUHSC  > 北京大学第一临床医学院  > 皮肤性病科
学科主题临床医学
Exome sequencing reveals mutation in GJA1 as a cause of keratoderma-hypotrichosis-leukonychia totalis syndrome
Wang, Huijun1,2,3; Cao, Xu1,2,3; Lin, Zhimiao1,2; Lee, Mingyang1,2; Jia, Xinying4; Ren, Yali5; Dai, Lanlan6,7; Guan, Liping6; Zhang, Jianguo6; Lin, Xuan8; Zhang, Jie1,2; Chen, Quan1,2; Feng, Cheng1,2; Zhou, Eray Yihui1,2; Yin, Jinghua1,2; Xu, Guiwen1,2; Yang, Yong1,2,3
刊名HUMAN MOLECULAR GENETICS
2015
DOI10.1093/hmg/ddu442
24期:1页:243-250
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Biochemistry & Molecular Biology ; Genetics & Heredity
资助者National Natural Science Foundation of China ; China Postdoctoral Science Foundation ; National Natural Science Foundation of China ; China Postdoctoral Science Foundation
研究领域[WOS]Biochemistry & Molecular Biology ; Genetics & Heredity
关键词[WOS]HIDROTIC ECTODERMAL DYSPLASIA ; DENTO-DIGITAL DYSPLASIA ; ICHTHYOSIS-DEAFNESS SYNDROME ; OCULODENTODIGITAL DYSPLASIA ; HEMICHANNEL ACTIVITY ; CONNEXIN-43 HEMICHANNELS ; PALMOPLANTAR KERATODERMA ; MISSENSE MUTATION ; READ ALIGNMENT ; GAP-JUNCTIONS
英文摘要

Keratoderma-hypotrichosis-leukonychia totalis syndrome (KHLS) is an extremely rare, autosomal-dominant disorder characterized by severe skin hyperkeratosis, congenital alopecia and leukonychia totalis. The genetic defect underlying KHLS remained undetermined. By performing whole-exome sequencing in a family with KHLS, we identified a heterozygous mutation (c.23G>T [p.Gly8Val]) in GJA1, which cosegregated with the phenotype in the family. In an additional affected individual, we also found the identical de novo mutation which was absent in his unaffected family members. GJA1 encodes a gap junction protein connexin 43 (Cx43) which is ubiquitously expressed in various organs, including the epidermis and hair follicles. In vitro studies on HEK293 cells expressing Cx43(GIY8Val) found that the protein formed gap junction plaques between adjacent transfected cells, as observed in the wild-type. Dye-transfer experiments by microinjection of Lucifer yellow displayed functional gap junction of the CX43(GIY8V) al mutant. Using patch clamp and Ca2+ imaging methods, we observed that the Cx43GIY8Val hemichannel had significantly more openings than Cx43(wT), facilitating Ca2+ influx at resting potential. Such gain-of-function effect might result in cytoplasmic Ca2+ overload, accelerated apoptosis of keratinocytes and subsequent skin hyperkeratosis. Taken together, our results demonstrated that, with probably enhanced hemichannel activities, a mutation in GJA1 is linked to KHLS without extracutaneous involvement.

语种英语
所属项目编号81271744 ; 81201220 ; 2013T60044
资助者National Natural Science Foundation of China ; China Postdoctoral Science Foundation ; National Natural Science Foundation of China ; China Postdoctoral Science Foundation
WOS记录号WOS:000350135400019
Citation statistics
Cited Times:13[WOS]   [WOS Record]     [Related Records in WOS]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/62840
Collection北京大学第一临床医学院_皮肤性病科
作者单位1.Beijing Key Lab Mol Diag Dermatoses, Beijing 100034, Peoples R China
2.Peking Tsinghua Ctr Life Sci, Beijing 100871, Peoples R China
3.Peking Univ, Hosp 1, Dept Dermatol, Beijing 100034, Peoples R China
4.Peking Univ, Hlth Sci Ctr, Dept Pathol, Beijing 100191, Peoples R China
5.Peking Univ, Hosp 1, Lab Electron Microscopy, Beijing 100034, Peoples R China
6.BGI Shenzhen, Shenzhen 518083, Peoples R China
7.BGI Shenzhen, Guangdong Enterprise Key Lab Human Dis Genom, Shenzhen 518083, Peoples R China
8.Cangshan Cty Peoples Hosp, Dept Dermatol, Cangshan 277700, Shandong, Peoples R China
Recommended Citation
GB/T 7714
Wang, Huijun,Cao, Xu,Lin, Zhimiao,et al. Exome sequencing reveals mutation in GJA1 as a cause of keratoderma-hypotrichosis-leukonychia totalis syndrome[J]. HUMAN MOLECULAR GENETICS,2015,24(1):243-250.
APA Wang, Huijun.,Cao, Xu.,Lin, Zhimiao.,Lee, Mingyang.,Jia, Xinying.,...&Yang, Yong.(2015).Exome sequencing reveals mutation in GJA1 as a cause of keratoderma-hypotrichosis-leukonychia totalis syndrome.HUMAN MOLECULAR GENETICS,24(1),243-250.
MLA Wang, Huijun,et al."Exome sequencing reveals mutation in GJA1 as a cause of keratoderma-hypotrichosis-leukonychia totalis syndrome".HUMAN MOLECULAR GENETICS 24.1(2015):243-250.
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