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Exome sequencing reveals mutation in GJA1 as a cause of keratoderma-hypotrichosis-leukonychia totalis syndrome
- Source :
- Human molecular genetics. 24(1)
- Publication Year :
- 2014
-
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.
- Subjects :
- Adult
Male
Heterozygote
Mutation, Missense
Connexin
Biology
medicine.disease_cause
Hypotrichosis
Nail Diseases
Keratoderma, Palmoplantar
Genetics
medicine
Missense mutation
Humans
Exome
Genetic Predisposition to Disease
Keratoderma
Molecular Biology
Genetics (clinical)
Exome sequencing
Mutation
High-Throughput Nucleotide Sequencing
General Medicine
Sequence Analysis, DNA
medicine.disease
Molecular biology
Pedigree
HEK293 Cells
Child, Preschool
Connexin 43
Leukonychia
Calcium
Female
Epidermis
Hair Follicle
Pigmentation Disorders
Congenital Alopecia
Subjects
Details
- ISSN :
- 14602083
- Volume :
- 24
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Human molecular genetics
- Accession number :
- edsair.doi.dedup.....c9d789d30d21c68522977729e35a9d14