A human keratin 10 knockout causes recessive epidermolytic hyperkeratosis

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Serval ID
serval:BIB_1A6BDB22FF55
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
A human keratin 10 knockout causes recessive epidermolytic hyperkeratosis
Journal
Human Molecular Genetics
Author(s)
Muller  F. B., Huber  M., Kinaciyan  T., Hausser  I., Schaffrath  C., Krieg  T., Hohl  D., Korge  B. P., Arin  M. J.
ISSN
0964-6906 (Print)
Publication state
Published
Issued date
04/2006
Volume
15
Number
7
Pages
1133-41
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Apr 1
Abstract
Epidermolytic hyperkeratosis (EHK) is a blistering skin disease inherited as an autosomal-dominant trait. The disease is caused by genetic defects of the epidermal keratin K1 or K10, leading to an impaired tonofilament network of differentiating epidermal cells. Here, we describe for the first time a kindred with recessive inheritance of EHK. Sequence analysis revealed a homozygous nonsense mutation of the KRT10 gene in the affected family members, leading to a premature termination codon (p.Q434X), whereas the clinically unaffected consanguineous parents were both heterozygous carriers of the mutation. Semi-quantitative RT-PCR and western blot analysis demonstrated degradation of the KRT10 transcript, resulting in complete absence of keratin K10 protein in the epidermis and cultured keratinocytes of homozygous patients. This K10 null mutation leads to a severe phenotype, clinically resembling autosomal-dominant EHK, but differing in form and distribution of keratin aggregates on ultrastructural analysis. Strong induction of the wound-healing keratins K6, K16 and K17 was found in the suprabasal epidermis, which are not able to compensate for the lack of keratin 10. We demonstrate that a recessive mutation in KRT10 leading to a complete human K10 knockout can cause EHK. Identification of the heterogeneity of this disorder has a major impact for the accurate genetic counseling of patients and their families and also has implications for gene-therapy approaches.
Keywords
3T3 Cells/cytology/metabolism Cells, Cultured Child Codon, Nonsense Epidermis/cytology/metabolism/ultrastructure Exons/genetics Female Fibroblasts/cytology/metabolism Fluorescent Antibody Technique *Genes, Recessive Genotype Homozygote Humans Hyperkeratosis, Epidermolytic/*genetics/metabolism/pathology Keratin-10 Keratins/*genetics/metabolism Male Mice Microscopy, Electron Models, Biological Pedigree Phenotype RNA, Messenger/genetics Skin/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
25/01/2008 16:35
Last modification date
25/09/2019 6:08
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