ULTRASTRUCTURAL-CHANGES RESULTING FROM KERATIN-9 GENE-MUTATIONS IN 2 FAMILIES WITH EPIDERMOLYTIC PALMOPLANTAR KERATODERMA

Palmoplantar keratoderma of Voerner type (or epidermolytic palmoplanta r keratoderma) is an autosomal dominant inherited disorder of keratini zation with histologic features of epidermolytic hyperkeratosis. We st udied members of two large unrelated kindreds with epidermolytic palmo plantar keratoderma, and biopsy specimens of lesional palmar skin from both families confirmed the histologic changes of epidermolytic hyper keratosis. Whorls of abnormally aggregated keratin filaments were seen ultrastructurally to be associated with signs of cellular disintegrat ion in spinous and granular cells. Direct sequencing of genomic DNA sa mples obtained from several members of each family established the sub stitution of a highly conserved arginine by tryptophan (R162W) in the 1A region of the alpha-helical rod domain of keratin 9. This arginine residue in a highly conserved region of keratins 1 and 10 is affected by disruptive missense point mutations in many patients with bullous i chthyosiform erythroderma. An equivalent position in the sole and palm restricted keratin 9 appears to be the mutation hot spot in epidermol ytic palmoplantar keratoderma. To date, R162W is the most prevalent ge netic defect reported in this genodermatosis.