Missense Mutations in Keratin 17 Cause Either Pachyonychia Congenita Type 2 or a Phenotype Resembling Steatocystoma Multiplex

Abstract

Pachyonychia congenita (PC) is a group of autosomal dominant ectodermal dysplasias in which the main phenotypic characteristic is hypertrophic nail dystrophy. In the Jackson-Lawler form (PC-2), pachyonychia is accompanied by multiple pilosebaceous cysts, natal teeth, and hair abnormalities. By direct sequencing of genomic PCR products, we report heterozygous K17 missense mutations in the same conserved protein motif in a further five PC-2 families (K17 N92S in one familial and three sporadic cases; K17 Y98D in one familial case) confirming that mutations in this gene are a common cause of PC-2. We also show heterozygous missense mutations in K17 (N92H and R94H) in two families diagnosed as steatocystoma multiplex. Mild nail defects were observed in some but not all of these patients on clinical re-evaluation of these families. All the K17 mutations reported here were shown to co-segregate with the disease in the pedigrees analyzed and were excluded from 100 unaffected, unrelated chromosomes by restriction enzyme analysis of K17 genomic PCR products. We conclude that phenotypic variation is observed with K17 mutations, as is the case with other keratin disorders.

Epithelial Structural Proteins of the Skin and Oral Cavity: Function in Health and Disease

“…For example, the K6/K16 pair is expressed in nails, palm and sole skin, the hair follicle, and oral mucosa, which are all affected in the Jadassohn-Lewandowsky form. All mutations reported to date lie in the helix initiation LA peptide (Bowden et al, 1995;McLean et al, 1995;Smith et al, 1997). In one family, affected individuals have a three-base-pair deletion within the helix initiation peptide of K6a which removes a highly conserved asparagine residue (Bowden et al, 1995); this K6 mutation is identical to the K4 mutation reported in two families with white sponge nevus .…”

“…In one family, affected individuals have a three-base-pair deletion within the helix initiation peptide of K6a which removes a highly conserved asparagine residue (Bowden et al, 1995); this K6 mutation is identical to the K4 mutation reported in two families with white sponge nevus . Other forms of non-epidermolytic PPK resulting from mutations in K16 and K17 have been reported that have only very mild nail abnormalities (Shamsher et al, 1995;Smith et al, 1997 (Ku et al, 1997).…”

Palmoplantar Keratoderma and Leukokeratosis anogenitalis: The Second Case of a New Disease

“…This entity is characterized by overcurvated and thickened nails, PPK, hyperkeratosis of knees and elbows and tiny cutaneous horns over different skin areas. Although pachyonychia congenita type 2 has been associated with mutations of K17 [12]and nail involvement may be of late onset [13], this syndrome is not likely to account for the pathologic findings in our case.…”

Steatocystoma Multiplex -A Rare Genetic Disorder:A Case Report and Review of Literature

“…Smith FJD have reported heterozygous missense mutations in K17(N 92 H and R 94 H) in two families who were diagnosed as steatocystoma multiplex [10].…”