Splice site and deletion mutations in keratin (KRT1 and KRT10) genes: unusual phenotypic alterations in Scandinavian patients with epidermolytic hyperkeratosis

Virtanen, Marie, Smith, Susan Kaye, Gedde-Dahl Jr, Tobias, Vahlquist, Anders and Bowden, Paul Edward 2003. Splice site and deletion mutations in keratin (KRT1 and KRT10) genes: unusual phenotypic alterations in Scandinavian patients with epidermolytic hyperkeratosis. Journal of investigative dermatology 121 (5) , pp. 1013-20. 10.1046/j.1523-1747.2003.12534.x

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Abstract

Epidermolytic hyperkeratosis is a rare autosomal dominant inherited skin disorder caused by keratin 1 or keratin 10 mutations. Keratins are major structural proteins of the epidermis, and in keratinocytes committed to terminal differentiation the intermediate filaments are composed of keratin 1 and keratin 10 heterodimers. The majority of reported mutations (86.6%) are heterozygous single point mutations and most of these are located in the 1A and 2B regions of the highly conserved keratin -helical rod domain. We have studied eight Scandinavian families with epidermolytic hyperkeratosis and identified three point mutations, two codon deletions, two splice site mutations, and a complex deletion/insertion. Two of the point mutations were in the KRT1 gene (F191C and K177N) and the other was in KRT10 (L453P). All three patients had associated palmoplantar keratoderma. The splice site mutations in KRT1 both caused a large deletion removing 22 codons (176–197) from the 1A helical domain. Codon deletions were found in KRT1 (170–173) and in KRT10 (161–162) in two patients with a severe phenotype. A final patient had a more complex mutation with a large deletion (442 bp) together with a large insertion (214 bp) of unknown origin that caused deletion of exon 6 in KRT1. In conclusion, we have found eight novel keratin mutations that cause epidermolytic hyperkeratosis with differing phenotypes. Even when a large part of keratin 1 (46 amino acids) is deleted, surprisingly mild phenotypes can result, suggesting that genotype-phenotype relationships in epidermolytic hyperkeratosis are complex and do not solely depend on the type of mutation but also depend on interactions between the behavior of the mutant protein and the cellular environment.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Uncontrolled Keywords:	Bullous congenital ichthyosiform erythroderma ; Gerodermatosis ; Palmoplantar keratoderma ; Intermediate filaments
Publisher:	Nature Publishing Group for the Society for Investigative Dermatology
ISSN:	15231747
Last Modified:	12 Jun 2019 02:22
URI:	https://orca.cardiff.ac.uk/id/eprint/444

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