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Human Molecular Genetics Advance Access published online on February 27, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl028
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received November 15, 2005
Revised February 10, 2006
Accepted February 10, 2006

Article

A human keratin 10 knockout causes recessive epidermolytic hyperkeratosis

Felix B. Müller 1 *, Marcel Huber 2, Tamar Kinaciyan 3, Ingrid Hausser 4, Christina Schaffrath 5, Thomas Krieg 5, Daniel Hohl 2, Bernhard P. Korge 5, and Meral J. Arin 5

1 Department of Dermatology, University of Cologne, 50924 Köln, Germany
2 Department of Dermatology, CHUV Lausanne, Switzerland
3 Department of Dermatology, Medical University of Vienna, Austria
4 Department of Dermatology, University of Heidelberg, Germany
5 Department of Dermatology, University of Cologne, Germany

* To whom correspondence should be addressed.
Felix B. Müller, E-mail: felix.mueller{at}uni-koeln.de


  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 keratins 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. Semiquantitative 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 that 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 counselling of patients and their families and also has implications for gene therapy approaches.


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