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Hum Mol Genet. 2015 Jan 1;24(1):243-50. doi: 10.1093/hmg/ddu442. Epub 2014 Aug 28.

Exome sequencing reveals mutation in GJA1 as a cause of keratoderma-hypotrichosis-leukonychia totalis syndrome.

Author information

1
Department of Dermatology, Peking University First Hospital, Beijing 100034, China Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China Peking-Tsinghua Center for Life Sciences, Beijing 100871, China.
2
Department of Dermatology, Peking University First Hospital, Beijing 100034, China Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China.
3
Department of Pathology, Peking University Health Science Center, Beijing 100191, China.
4
Laboratory of Electron Microscopy, Peking University First Hospital, Beijing 100034, China.
5
BGI-Shenzhen, Shenzhen 518083, China The Guangdong Enterprise Key Laboratory of Human Disease Genomics, BGI-Shenzhen, Shenzhen 518083, China and.
6
BGI-Shenzhen, Shenzhen 518083, China.
7
Department of Dermatology, Cangshan County People's Hospital, Cangshan 277700 Shandong, China.
8
Department of Dermatology, Peking University First Hospital, Beijing 100034, China Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China Peking-Tsinghua Center for Life Sciences, Beijing 100871, China dryongyang@bjmu.edu.cn.

Abstract

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(Gly8Val) 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(Gly8Val) mutant. Using patch clamp and Ca(2+) imaging methods, we observed that the Cx43(Gly8Val) hemichannel had significantly more openings than Cx43(WT), facilitating Ca(2+) influx at resting potential. Such gain-of-function effect might result in cytoplasmic Ca(2+) 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.

PMID:
25168385
DOI:
10.1093/hmg/ddu442
[Indexed for MEDLINE]

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