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

Abstract

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 (psiKRT16B and psiKRT16C), 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.

Focal palmoplantar and gingival keratosis: A distinct palmoplantar ectodermal dysplasia with epidermolytic alterations but lack of mutations in known keratins

“…28,29 By contrast, the epidermolytic changes seen in the palmoplantar skin and less pronounced in the oral epithelium of pachyonychia congenita type I are caused by mutations of keratins 6A and 16. [30][31][32] Keratin 16 mutations were also reported in two families with focal nonepidermolytic palmoplantar keratoderma with oral, genital, and follicular lesions. 23,24 The absence of epidermolysis in this syndrome is thought to be caused by less disruptive keratin 16 mutations than in type I pachyonychia congenita.…”

Disadhesion of epidermal keratinocytes: A histologic clue to palmoplantar keratodermas caused by DSG1 mutations

“…Ultrastructural examination of a family with pachyonychia type I associated with a KRT16 mutation revealed keratin filaments that were greatly condensed but did not form the dense amorphous aggregates seen in a number of other keratin disorders. 26 Shamsher et al 27 described two families with autosomal-dominant disorder of focal nonepidermolytic PPK associated with heterozygous mutations in KRT16. These mutations did not appear to cause epidermolysis on light or electron microscopy.…”

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

“…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].…”

“…A number of more unusual symptoms have been reported in a few cases of PC [3] and in some cases in this study (Table 1). Interestingly, family 16 (K16 c.1052_1059+16del24) and three unrelated families (families [17][18][19] carrying mutation K16 p.Asn125Ser had a slightly different clinical presentation. Specifically, individuals in these families either had normal nails or very subtle nail changes, such as splinter haemorrhages, that developed later than in most classical cases of PC-1.…”