The genetic basis of Weber-Cockayne epidermolysis bullosa simplex.

YM Chan, QC Yu, JD Fine… - Proceedings of the …, 1993 - National Acad Sciences
YM Chan, QC Yu, JD Fine, E Fuchs
Proceedings of the National Academy of Sciences, 1993National Acad Sciences
Epidermolysis bullosa simplex (EBS) is a group of autosomal dominant skin diseases
characterized by blistering, due to mechanical-stress-induced degeneration of basal
epidermal cells. Recently, it was discovered that the more severe types, Dowling-Meara and
Koebner, are genetic disorders of the basal epidermal keratins, keratin 5 (K5) and keratin 14
(K14). Here, we show that the mildest type of EBS, Weber-Cockayne, is also a disorder of
these keratins. Affected members of two unrelated families with Weber-Cockayne EBS had a …
Epidermolysis bullosa simplex (EBS) is a group of autosomal dominant skin diseases characterized by blistering, due to mechanical-stress-induced degeneration of basal epidermal cells. Recently, it was discovered that the more severe types, Dowling-Meara and Koebner, are genetic disorders of the basal epidermal keratins, keratin 5 (K5) and keratin 14 (K14). Here, we show that the mildest type of EBS, Weber-Cockayne, is also a disorder of these keratins. Affected members of two unrelated families with Weber-Cockayne EBS had a T-->G point mutation in the second base position of codon 161 of one of two K5 alleles, leading to an Ile-->Ser mutation. This mutation was not present in unaffected members or in 156 alleles from normal individuals. Linkage analyses mapped the defect to the type II keratin gene cluster on chromosome 12q11-q13 (peak logarithm of odds score at theta = 0 of 3.0), providing strong additional evidence that this mutation is responsible for the Weber-Cockayne EBS phenotype. Conserved among type II keratins, Ile-161 is in the nonhelical head domain of K5, a region previously shown to be important for 10-nm filament assembly. The mutation generates a potential substrate site for protein kinase C, which could influence intermediate filament architecture, perhaps leading to the intrafilament association seen ultrastructurally in patients with the mutation.
National Acad Sciences