Human Molecular Genetics Advance Access originally published online on February 27, 2006
Human Molecular Genetics 2006 15(7):1133-1141; doi:10.1093/hmg/ddl028
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A human keratin 10 knockout causes recessive epidermolytic hyperkeratosis
1Department of Dermatology, University of Cologne, 50924 Köln, Germany, 2Department of Dermatology, CHUV Lausanne, Switzerland, 3Department of Dermatology, Medical University of Vienna, Austria and 4Department of Dermatology, University of Heidelberg, Germany
* To whom correspondence should be addressed: Tel: +49 2214785984; Fax: +49 2214785949; Email: felix.mueller{at}uni-koeln.de
Received November 15, 2005; Accepted February 10, 2006
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.
The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.