| Title | Exome sequencing reveals mutation in GJA1 as a cause of keratoderma-hypotrichosis-leukonychia totalis syndrome |
| Authors | Wang, Huijun Cao, Xu Lin, Zhimiao Lee, Mingyang Jia, Xinying Ren, Yali Dai, Lanlan Guan, Liping Zhang, Jianguo Lin, Xuan Zhang, Jie Chen, Quan Feng, Cheng Zhou, Eray Yihui Yin, Jinghua Xu, Guiwen Yang, Yong |
| Affiliation | Peking Univ, Hosp 1, Dept Dermatol, Beijing 100034, Peoples R China. Beijing Key Lab Mol Diag Dermatoses, Beijing 100034, Peoples R China. Peking Tsinghua Ctr Life Sci, Beijing 100871, Peoples R China. Peking Univ, Hlth Sci Ctr, Dept Pathol, Beijing 100191, Peoples R China. Peking Univ, Hosp 1, Lab Electron Microscopy, Beijing 100034, Peoples R China. BGI Shenzhen, Shenzhen 518083, Peoples R China. BGI Shenzhen, Guangdong Enterprise Key Lab Human Dis Genom, Shenzhen 518083, Peoples R China. Cangshan Cty Peoples Hosp, Dept Dermatol, Cangshan 277700, Shandong, Peoples R China. Peking Univ, Hosp 1, Dept Dermatol, 8 Xishiku St, Beijing 100034, Peoples R China. |
| Keywords | HIDROTIC ECTODERMAL DYSPLASIA DENTO-DIGITAL DYSPLASIA ICHTHYOSIS-DEAFNESS SYNDROME OCULODENTODIGITAL DYSPLASIA HEMICHANNEL ACTIVITY CONNEXIN-43 HEMICHANNELS PALMOPLANTAR KERATODERMA MISSENSE MUTATION READ ALIGNMENT GAP-JUNCTIONS |
| Issue Date | 2015 |
| Publisher | human molecular genetics |
| Citation | HUMAN MOLECULAR GENETICS.2015,24,(1),243-250. |
| 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(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. |
| URI | http://hdl.handle.net/20.500.11897/304020 |
| ISSN | 0964-6906 |
| DOI | 10.1093/hmg/ddu442 |
| Indexed | SCI(E) PubMed |
| Appears in Collections: | 第一医院 |
