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 cl inical subtypes, PC-1 and PC-2, are inherited as autosomal dominant disorde rs, but other less well characterized clinical forms also exist. The PC-1 p henotype map be distinguished by the absence of the epidermal cysts found i n PC-2, and it has been shown to be caused by mutations in either keratin K 16 or its expression partner, the K6a isoform of K6, Mutations in K16 have also been shown to cause a milder related phenotype, focal non-epidermolyti c palmoplantar keratoderma. Recently, we have developed a long-range polyme rase chain reaction (PCR) strategy which allows specific amplification of t he entire functional K16 gene (KRT16A), without amplification of the two K1 6 pseudogenes (psi KRT16B and psi 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 wi th PC-1, Both mutations were excluded from 50 normal unrelated individuals by restriction enzyme analysis of K16 PCR fragments. In one family, ultrast ructural analysis was performed. revealing distinctive tonofilament abnorma lities. Specifically, keratin filament bundles were greatly condensed, but did not form the dense amorphous aggregates seen in a number of other kerat in disorders. In the second. kindred, autosomal dominant cataract was prese nt in some but not all members affected by PC. As the cataract phenotype di d not fully cosegregate with the K16 mutation, and given that K16 is not ex pressed in the lens, these two phenotypes may be coincidental.