THE GENETIC-BASIS OF EPIDERMOLYSIS-BULLOSA SIMPLEX WITH MOTTLED PIGMENTATION

Epidermolysis bullosa simplex (EBS) is a group of autosomal dominant s kin diseases characterized by blistering, due to mechanical stress-ind uced degeneration of basal epidermal cells, It is now well-established that the three major subtypes of EBS are genetic disorders of the bas al epidermal keratins, keratin 5 (K5) and keratin 14 (K14). Here we sh ow that a rare subtype, referred to as EBS with mottled pigmentation ( MP), is also a disorder of these keratins, Affected members of two see mingly unrelated families with EBS-MP had a C to T point mutation in t he second base position of codon 24 of one of two K5 alleles, leading to a Pro:Leu mutation. This mutation was not present in unaffected mem bers nor in 100 alleles from normal individuals. Linkage analyses mapp ed the defect to this type II keratin gene (peak logarithm of odds sco re at phi = 0 of 3.9), which is located on chromosome 12q11-q13. This provides strong evidence that this mutation is responsible for the EBS -MP phenotype, Only conserved between K5 and K6, and not among any of the other type II keratins, Pro-24 is in the nonhelical head domain of K5, and only mildly perturbs the length of 10-nm keratin filaments as sembled in vitro, However, this part of the K5 head domain is likely t o protrude on the filament surface, perhaps leading to additional aber rations in intermediate filament architecture and/or in melanosome dis tribution that are seen ultrastructurally in patients with the mutatio n.