Mutations in the 1A Domain of Keratin 9 in Patients with Epidermolytic Palmoplantar Keratoderma

Abstract

Epidermolytic palmoplantar keratoderma is an autosomal dominant skin disorder characterized by hyperkeratosis of the palms and soles. Ultrastructurally the disease exhibits abnormal keratin filament networks and tonofilament clumping like that found in the keratin disorders of epidermolysis bullosa simplex and epidermolytic hyperkeratosis. The disease has been mapped to chromosome 17q11-q23 in the region of the type 1 keratin gene locus and more recently mutations have been found in the palmoplantar specific keratin, keratin 9. We have analyzed six unrelated incidences of epidermolytic palmoplantar keratoderma for mutations in their keratin 9 genes. In two of these, we have identified mutations that alter critical residues within the highly conserved helix initiation motif at the beginning of the rod domain of keratin 9. In a three-generation Middle Eastern kindred we found a C to T transition at codon 162 that results in an arginine to tryptophan substitution at position 10 of the 1A alpha-helical domain, thus confirming this codon as a hot spot for mutation in keratin 9. The other mutation found involves a T to C transition at codon 167 that results in the expression of a serine residue in place of the normal leucine at position 15 of the 1A segment and is the first documentation of this mutation in this gene. The identification of these substitutions extends the current catalog of disease causing mutations in keratin 9.

Keratin 9 point mutation in the pedigree of epidermolytic hereditary palmoplantar keratoderma perturbs keratin intermediate filament network formation

“…In previous reports on the K9 mutation, eight types of point mutations were reported [4][5][6][7][8] as summarized in Fig. 3. (1) M156V: substitution of valine for methionine at amino acid 156 by A to G transition at nt 532 [6]; (2) N160Y: substitution of tyrosine for asparagine at amino acid 160 by the transversion of A to T at nt 544 [4]; (3) N160S: serine for asparagine at 160 by the transversion of A to G transition at nt 545 [7]; (4) N160K: lysine for asparagine at 160 by T to A transversion at nt 546 [5]; (5) R162W: tryptophan for arginine at 162 by C to T transition at nt 550 [5,7,8]; (6) R162Q: glutamine for arginine at 162 by G to A transition at nt 551 [5] (our cases have the same amino acid mutation of glutamine for arginine); (7) L167S: serine for leucine at 167 by transition of T to C at nt 566 [8]; and (8) Q171P: substitution of proline of glutamine at 171 by A to C transversion at nt 578 [6]. Thus, amino acids 156-171, which correspond to the head of the c~-helical domain of keratin intermediate filaments, may be a hot spot of mutation and the replacement of these amino acids may be crucial for keratin filament assembly and intermediate filament network formation in the cells.…”

“…There are previous reports of *Corresponding author. Fax: (81) (75) 761-3002; E-mail : tanakat@kuhp.kyoto-u.ac.jp Abbreviations: EHPPK, epidermolytic hereditary palmoplantar keratoderma; IF, intermediate filament; K9, keratin 9; PCR, polymerase chain reaction; HA, hemagglutinin protein of influenza; K14, keratin 14; EBS, epidermolysis bullosa simplex point mutations in the K9 gene in EHPPK [4][5][6][7][8] but none showed a function assay with these mutations. Here, we provide the first demonstration that the point mutation found in a pedigree of EHPPK has a dominant-negative effect on the assembly of keratin intermediate filaments in the cells.…”

Complete Cytolysis and Neonatal Lethality in Keratin 5 Knockout Mice Reveal Its Fundamental Role in Skin Integrity and in Epidermolysis Bullosa Simplex

“…These mutations cause a number of inherited human skin disorders such as epidermolysis bullosa simplex (EBS) (Bonifas et al, 1991;Coulombe et al, 1991;Lane et al, 1992;Rothnagel et al, 1995;Corden and McLean, 1996). The characteristic feature of EBS is epidermal blistering resulting from cytolysis of basal keratinocytes.…”

Les kératodermies palmo-plantaires héréditaires

“…Ultérieurement, de nombreuses équipes ont identifié des mutations ponctuelles et différentes au niveau du gène codant pour la kératine 9 [9,39,67,86,105,124,131,144]. La mutation du codon R 162 W apparaît comme la plus fréquente [105].…”