Novel proline substitution mutations in keratin 16 in two cases of pachyonychia congenita type 1

Pachyonychia congenita (PC) is a group of inherited ectodermal dysplasias, the characteristic phenotype being hypertrophic nail dystrophy. Two main clinical subtypes, PC‐1 and PC‐2, are inherited as autosomal dominant disorders, but other less well characterized clinical forms also exist. The PC‐1 phenotype may be distinguished by the absence of the epidermal cysts found in PC‐2, and it has been shown to be caused by mutations in either keratin K16 or its expression partner, the K6a isoform of K6. Mutations in K16 have also been shown to cause a milder related phenotype, focal non‐epidermolytic palmoplantar keratoderma. Recently, we have developed a long‐range polymerase chain reaction (PCR) strategy which allows specific amplification of the entire functional K16 gene ( KRT16A ), without amplification of the two K16 pseudogenes (ψ KRT16B and ψ KRT16C ), enabling mutation analysis based on genomic DNA. Here, using this methodology, we describe novel mutations R127P and Q122P in the helix 1A domain of K16 in two families presenting with PC‐1. Both mutations were excluded from 50 normal unrelated individuals by restriction enzyme analysis of K16 PCR fragments. In one family, ultrastructural analysis was performed, revealing distinctive tonofilament abnormalities. Specifically, keratin filament bundles were greatly condensed, but did not form the dense amorphous aggregates seen in a number of other keratin disorders. In the second kindred, autosomal dominant cataract was present in some but not all members affected by PC. As the cataract phenotype did not fully cosegregate with the K16 mutation, and given that K16 is not expressed in the lens, these two phenotypes may be coincidental.