Identification of novel and known mutations in the genes for keratin 5 and14 in Danish patients with epidermolysis bullosa simplex: Correlation between genotype and phenotype

Epidermolysis bullosa simplex (EBS) is a group of autosomal dominant inheri ted skin diseases caused by mutations in either the keratin 5 (K5) or the k eratin 14 (K14) genes and characterized by development of intraepidermal sk in blisters. The three major subtypes of EBS are Weber-Cockayne, Koebner, a nd Dowling-Meara, of which the Dowling-Meara form is the most severe. We ha ve investigated five large Danish families with EBS and two sporadic patien ts with the Dowling-Meara form of EBS, In the sporadic Dowling-Meara EBS pa tients, a novel K14 mutation (N123S) and a previously published K5 mutation (N176S) were identified, respectively. A novel K14 mutation (K116N) was fo und in three seemingly unrelated families, whereas another family harbored a different novel K14 mutation (L143P). The last family harbored a novel K5 mutation (L325P), The identified mutations were not present in more than 1 00 normal chromosomes, Six polymorphisms were identified in the K14 gene an d their frequencies were determined in normal controls. These polymorphisms were used to show that the K14 K116N mutation was located in chromosomes w ith the same haplotype in all three families, suggesting a common ancestor. We observed a strict genotype-phenotype correlation in the investigated pa tients as the same mutation always resulted in a similar phenotype in all i ndividuals with the mutation, but our results also show that it is not poss ible to predict the EBS phenotype merely by the location (i.e., head, rod, or linker domains) of a mutation. The nature of the amino acid substitution must also be taken into account.