Exome sequencing reveals mutation in GJA1 as a cause of keratoderma-hypotrichosis-leukonychia totalis syndrome.
Exome sequencing reveals mutation in GJA1 as a cause of keratoderma-hypotrichosis-leukonychia totalis syndrome.
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外显子组测序揭示 GJA1 突变是角化病-少毛症-全白甲综合征的病因。
DOI：
10.1093/hmg/ddu442
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发表时间：
2015
影响因子：
3.5
通讯作者：
Yang, Yong
中科院分区：
文献类型：
--
作者：
Zhou, Eray Yihui;Yin, Jinghua;Xu, Guiwen;Yang, Yong
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.
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影响因子：
14.8
作者：
Kumar, Prateek;Henikoff, Steven;Ng, Pauline C.
通讯作者：
Ng, Pauline C.
DOI：
10.1038/jid.2008.335
发表时间：
2009-04
期刊：
The Journal of investigative dermatology
影响因子：
--
作者：
Lee JR;Derosa AM;White TW
通讯作者：
White TW
DOI：
10.1007/bf00187825
发表时间：
1995-03
期刊：
Anatomy and Embryology
影响因子：
--
作者：
E. Dahl;Elke Winterhager;Otto Traub;Klaus Willecke
通讯作者：
E. Dahl;Elke Winterhager;Otto Traub;Klaus Willecke
DOI：
10.1042/bj20110278
发表时间：
2011-09
期刊：
The Biochemical journal
影响因子：
--
作者：
C. Scott;D. Kelsell
通讯作者：
C. Scott;D. Kelsell
DOI：
--
发表时间：
2006-05
期刊：
European journal of dermatology : EJD
影响因子：
--
作者：
S. C. Kelly;P. Ratajczak;M. Keller;S. Purcell;T. Griffin;G. Richard
通讯作者：
S. C. Kelly;P. Ratajczak;M. Keller;S. Purcell;T. Griffin;G. Richard