A mutation in human keratin K6b produces a phenocopy of the K17 disorder pachyonychia congenita type 2

Type I and type II keratins form the heteropolymeric intermediate filamentcytoskeleton, which is the main stress-bearing structure within epithelialcells. Pachyonychia congenita (PC) is a group of autosomal dominantdisorders whose most prominent phenotype is hypertrophic nail dystrophyaccompanied by other features of ectodermal dysplasia. It has been shownpreviously that mutations in either K16 or K6a, which form a keratinexpression pair, produce the PC-1 variant (MIM 184510). Mutations in K17alone, an unpaired accessory keratin, result in the PC-2 phenotype (MIM184500). Here, we describe a family with PC-2 in which the K17 locus on 17qwas excluded and linkage to the type II keratin locus on 12q was obtained(Z max 3.31 at straight theta = 0). Mutation analysis of candidate keratinsrevealed the first reported missense mutation in K6b, implying that thiskeratin is the previously unknown expression partner of K17, analogous tothe K6a/K16 pair. Co-expression of these genes was confirmed by in situhybridization and immunohistochemical staining. These results reveal thehitherto unknown role of the K6b isoform in epithelial biology, as well asgenetic heterogeneity in PC-2.