A KERATIN-14 MUTATIONAL HOT-SPOT FOR EPIDERMOLYSIS-BULLOSA SIMPLEX, DOWLING-MEARA - IMPLICATIONS FOR DIAGNOSIS

Recently, two patients with the Dowling-Meara subtype of epidermolysis bullosa simplex (EBS-DM) were reported with different mutations in co don 125 of the keratin 14 gene. To determine whether these are common mutations, we screened ten EBS-DM patients and their families using si ngle nucleotide primer extension. Four of ten unrelated EBS-DM patient s had a G --> A substitution at base pair 434 of codon 125, whereas on e case out of ten had a C --> T substitution at position 433 of the sa me codon. The G434A alteration cosegregated with the disorder in two m ultigenerational families; no recombination events were detected. In t hese two families, linkage analysis provided significant evidence in f avor of linkage between G434A and the EBS-DM phenotype, with a LOD sco re of 3.29 at a recombination rate of 0%. Codon 125 substitutions iden tified in three unrelated sporadic EBS-DM patients were not found in t heir clinically unaffected parents. Together, these data provide compe lling genetic evidence that the codon 125 substitutions are causal for EBS-DM. The high frequency of mutation at this site in individuals wi th EBS-DM now makes DNA-based diagnosis of this disorder feasible.