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

SummaryBackgroundPachyonychia congenita (PC) is a rare autosomal dominant keratin disorder, subdivided into two major variants, PC-1 and PC-2. Predominant characteristics include hypertrophic nail dystrophy, focal palmoplantar keratoderma and oral leukokeratosis. Multiple steatocystomas that develop during puberty are a useful feature distinguishing PC-2 from PC-1. At the molecular level it has been shown that mutations in keratin K6a or K16 cause PC-1 whereas those in K6b or K17 lead to PC-2.ObjectiveTo identify mutations in 22 families presenting with clinical symptoms of either PC-1/focal non-epidermolytic palmoplantar keratoderma (FNEPPK) or PC-2.MethodsMutation analysis was performed on genomic DNA from PC patients by direct sequencing.ResultsHere, we report four new missense and five known mutations in K6a; one new deletion and three previously identified missense mutations in K16; plus one known mutation in K17.ConclusionWith one exception, all these heterozygous mutations are within the highly conserved helix boundary motif regions at either end of the keratin rod domain. In one sporadic case, a unique mutation in K16 resulting in deletion of 24 bp was found within the central rod domain, in a child with a phenotype predominantly consisting of focal plantar keratoderma. The identification of mutations in cases of PC is prerequisite for future development of gene-specific and/or mutation-specific therapies.