Insights into Genotype–Phenotype Correlation in Pachyonychia Congenita from the Human Intermediate Filament Mutation Database

Abstract

Keratins are the intermediate filament proteins specifically expressed by epithelial cells. The Human Genome Project has uncovered a total of 54 functional keratin genes that are differentially expressed in specific epithelial structures of the body, many of which involve the epidermis and its appendages. Pachyonychia congenita (PC) is a group of autosomal dominant genodermatoses affecting the nails, thick skin and other ectodermal structures, according to specific sub-type. The major clinical variants of the disorder (PC-1 and PC-2) are known to be caused by dominant-negative mutations in one of four differentiation-specific keratins: K6a, K6b, K16, and K17. A total of 20 human keratin genes are currently linked to single-gene disorders or are predisposing factors in complex traits. In addition, a further six intermediate filament genes have been linked to other non-epithelial genetic disorders. We have established a comprehensive mutation database that catalogs all published independent occurrences of intermediate filament mutations (http://www.interfil.org), with details of phenotypes, published papers, patient support groups and other information. Here, we review the genotype-phenotype trends emerging from the spectrum of mutations in these genes and apply these correlations to make predictions about PC phenotypes based on the site of mutation and keratin pair involved.

A spectrum of mutations in keratins K6a, K16 and K17 causing pachyonychia congenita

“…A number of more unusual symptoms have been reported in a few cases of PC [3] and in some cases in this study (Table 1). Interestingly, family 16 (K16 c.1052_1059+16del24) and three unrelated families (families [17][18][19] carrying mutation K16 p.Asn125Ser had a slightly different clinical presentation. Specifically, individuals in these families either had normal nails or very subtle nail changes, such as splinter haemorrhages, that developed later than in most classical cases of PC-1.…”

The molecular basis of human keratin disorders

“…The functional consequences at the protein level are expression of mutant polypeptides at normal or near-normal levels with amino acid substitutions, deletions or insertion of a foreign amino acid. The mutant proteins form heterodimers with the wildtype keratin partner and thereby integrate into the keratin network where they render the cytoskeleton susceptible to collapse when exposed to environmental stress (McLean et al 2005).…”

Epidermolysis Bullosa Simplex

“…18, 77 Molecular diagnosis is generally conducted in a stepwise fashion, with screening beginning by mutation analysis of KRT5 and KRT14 conserved regions; data collected in Western populations have shown that more than 40% of EBS cases are caused by a mutation affecting the KRT14 R125 residue. 78,79 The existence of KRT14 pseudogenes requires the use of special techniques to avoid amplification of nonrelevant sequences. 80 If no mutation is identified in the conserved regions of the two genes, sequence alterations are looked …”