Novel and Recurrent Mutations in the Genes Encoding Keratins K6a, K16 and K17 in 13 Cases of Pachyonychia Congenita

Abstract

Thirteen patients with pachyonychia congenita types 1 and 2 were studied, two of which had a family history of pachyonychia and 11 of which were sporadic cases. Heterozygous mis-sense or small in-frame insertion/deletion mutations were detected in the genes encoding keratins K6a, K16, and K17 in all cases. Three novel mutations, F174V, E472K, and L469R were found in the K6a gene. Two novel mutations, M121T and L128Q were detected in K16. Similarly, three novel mutations, L95P, S97del, and L99P were found in K17. In addition, we identified recurrent mutations N171del (three instances) and F174S in K6a and R94H in K17. Analysis of both phenotype and genotype data led to the following conclusions: (i) K6a or K16 mutations produce the pachyonychia congenita type 1 phenotype, whereas K17 (or K6b) mutations cause pachyonychia congenita type 2; (ii) the presence of pilosebaceous cysts following puberty is the best indicator of pachyonychia congenita type 2; (iii) prepubescent patients are more difficult to classify due to the lack of cysts; and (iv) natal teeth are indicative of pachyonychia congenita type 2, although their absence does not preclude the pachyonychia congenita type 2 phenotype. This study establishes useful diagnostic criteria for pachyonychia congenita types 1 and 2, which will help limit unnecessary DNA analysis in the diagnosis and management of this genetically heterogeneous group of genodermatoses.

A Novel Mutation in the Second Half of the Keratin 17 1A Domain in a Large Pedigree with Delayed-Onset Pachyonychia Congenita Type 2

“…We have identified a novel mutation (N109D) located in the second half of the 1A domain (N25D in the 1A domain) of K17 in a Chinese pedigree with delayed-onset PC-2. To date and including this report, 24 independent mutations have been described in patients with either PC-2 or steatocystoma multiplex Fujimoto et al, 1998;Celebi et al, 1999;Smith et al, 2001;Terrinoni et al, 2001;Wang et al, 2001;Hashiguchi et al, 2002;Feng et al, 2003; www.interfil.org). They were located in the helix initiation 1A domain of K17 (Fig 2).…”

A Missense Mutation within the Helix Initiation Motif of the Keratin K71 Gene Underlies Autosomal Dominant Woolly Hair/Hypotrichosis

“…Phe141 (amino-acid position 12 in the HIM) is fully conserved among all human type II keratins (Figure 3b). Furthermore, substitutions at amino-acid position 12 in the HIM of other type II keratins underlie several AD genodermatoses in humans (Stephens et al, 1997;Smith et al, 1999;Terrinoni et al, 2001;Virtanen et al, 2001;Liao et al, 2007) (Supplementary Table S1 online). Of these, substitutions from Phe to Cys at this amino-acid position have been found in K1 and K6A proteins as pathogenic mutations for epidermolytic hyperkeratosis and pachyonychia congenita type 1, respectively (Virtanen et al, 2001;Liao et al, 2007) (Supplementary Table S1 online).…”

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

“…3). Five previously identified mutations were found in K6a (p.Asn171Ser Â3, p.Asn172del Â3, p.Leu469Pro, p.Leu469Arg and p.Glu472Lys Â2) [13,16]. Note that according to the recently revised mutation nomenclature K6a p.Asn172del is the correct numbering for the mutation that was previously denoted K6aAsn171del in several earlier publications.…”

“…This is predicted to lead to a deletion of 42 amino acids from the 2B domain of the K16 protein which would be consistent with the diagnosis of dominant PC-1 or a related FNEPPK phenotype. Known mutations found in K16 were p.Asn125Ser Â3, p.Arg127Pro and p.Leu128Gln [13,16,17]. The single PC-2 family analysed had the most commonly reported mutation in K17, p.Asn92-Ser [13].…”