title: Exome sequencing reveals mutation in GJA1 as a cause of keratoderma-hypotrichosis-leukonychia totalis syndrome.
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.
authors.affiliation: 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.
authors.forename: Huijun
authors.initials: H
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Xu
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Dermatology, Peking University First Hospital, Beijing 100034, China Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China.
authors.forename: Zhimiao
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Department of Dermatology, Peking University First Hospital, Beijing 100034, China Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China.
authors.forename: Mingyang
authors.initials: M
authors.lastname: Lee
authors.affiliation: Department of Pathology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Xinying
authors.initials: X
authors.lastname: Jia
authors.affiliation: Laboratory of Electron Microscopy, Peking University First Hospital, Beijing 100034, China.
authors.forename: Yali
authors.initials: Y
authors.lastname: Ren
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China The Guangdong Enterprise Key Laboratory of Human Disease Genomics, BGI-Shenzhen, Shenzhen 518083, China and.
authors.forename: Lanlan
authors.initials: L
authors.lastname: Dai
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Guan
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Dermatology, Cangshan County People's Hospital, Cangshan 277700 Shandong, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Dermatology, Peking University First Hospital, Beijing 100034, China Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Dermatology, Peking University First Hospital, Beijing 100034, China Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Dermatology, Peking University First Hospital, Beijing 100034, China Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Feng
authors.affiliation: Department of Dermatology, Peking University First Hospital, Beijing 100034, China Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China.
authors.forename: Eray Yihui
authors.initials: EY
authors.lastname: Zhou
authors.affiliation: Department of Dermatology, Peking University First Hospital, Beijing 100034, China Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Yin
authors.affiliation: Department of Dermatology, Peking University First Hospital, Beijing 100034, China Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China.
authors.forename: Guiwen
authors.initials: G
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000328:Adult; D002118:Calcium / Q000378:metabolism*; D002675:Child, Preschool; D018031:Connexin 43 / Q000235:genetics* / Q000378:metabolism*; D004817:Epidermis / Q000378:metabolism; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D018859:Hair Follicle / Q000378:metabolism; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007039:Hypotrichosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D007645:Keratoderma, Palmoplantar / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D020125:Mutation, Missense; D009260:Nail Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D010375:Pedigree; D010859:Pigmentation Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D017422:Sequence Analysis, DNA
chemical_list: D018031:Connexin 43; C500216:GJA1 protein, human; D002118:Calcium