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Novel keratin 16 mutations and protein expression studies in pachyonychia congenita type 1 and focal palmoplantar keratoderma

Lookup NU author(s): Dr Eugene Healy, Professor Jonathan Rees


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Pachyonychia congenita type 1 (PC-1) is an autosomal dominant ectodermal dysplasia characterized by nail dystrophy, focal non-epidermolytic palmoplantar keratoderma (FNEPPK) and oral lesions. We have previously shown that mutations in keratin 16 (K16) cause fragility of specific epithelia resulting in phenotypes of PC-1 or FNEPPK alone. Here, we report 2 novel mutations in K16 causing distinct phenotypes. A heterozygous missense mutation (L124R) was detected in a kindred with PC-1. In a family where mild FNEPPK was the only phenotype, a 23 bp deletion and a separate 1 bp deletion downstream were found in exon 6: [1244-1266del; 1270delG]. At the protein level, these mutations remove 8 residues and substitute 2 residues in the helix termination motif (HTM) of the K16 polypeptide. The HTM sequence is conserved in all known intermediate filament proteins and for convenience, this complex mutation was designated ΔHTM. Transient expression of K16 cDNAs carrying either the L124R or the ΔHTM mutation in epithelial cell line PtK2 produced aggregation of the keratin cytoskeleton. However, the aggregates observed with the ΔHTM mutation were morphologically different and appeared to be less disruptive to the endogenous cytoskeleton. Therefore, loss of the HTM sequence may render this mutant K16 less capable of contributing to filament assembly and decrease its dominant-negative effect, resulting in the milder FNEPPK phenotype.

Publication metadata

Author(s): Smith FJD, Fisher MP, Healy E, Rees JL, Bonifas JM, Epstein Jr EH, Tan EML, Uitto J, McLean WHI

Publication type: Article

Publication status: Published

Journal: Experimental Dermatology

Year: 2000

Volume: 9

Issue: 3

Pages: 170-177

ISSN (print): 0906-6705

ISSN (electronic): 1600-0625

Publisher: Wiley-Blackwell Publishing Ltd.


DOI: 10.1034/j.1600-0625.2000.009003170.x

PubMed id: 10839714


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