title: A keratin 14 mutational hot spot for epidermolysis bullosa simplex, Dowling-Meara: implications for diagnosis.
abstract: Recently, two patients with the Dowling-Meara subtype of epidermolysis bullosa simplex (EBS-DM) were reported with different mutations in codon 125 of the keratin 14 gene. To determine whether these are common mutations, we screened ten EBS-DM patients and their families using single nucleotide primer extension. Four of ten unrelated EBS-DM patients had a G-->A substitution at base pair 434 of codon 125, whereas one case out of ten had a C-->T substitution at position 433 of the same codon. The G434A alteration cosegregated with the disorder in two multigenerational families; no recombination events were detected. In these two families, linkage analysis provided significant evidence in favor of linkage between G434A and the EBS-DM phenotype, with a LOD score of 3.29 at a recombination rate of 0%. Codon 125 substitutions identified in three unrelated sporadic EBS-DM patients were not found in their clinically unaffected parents. Together, these data provide compelling genetic evidence that the codon 125 substitutions are causal for EBS-DM. The high frequency of mutation at this site in individuals with EBS-DM now makes DNA-based diagnosis of this disorder feasible.
authors.affiliation: Department of Medicine, University of Washington, Seattle 98195.
authors.forename: K
authors.initials: K
authors.lastname: Stephens
authors.forename: V P
authors.initials: VP
authors.lastname: Sybert
authors.forename: E M
authors.initials: EM
authors.lastname: Wijsman
authors.forename: P
authors.initials: P
authors.lastname: Ehrlich
authors.forename: A
authors.initials: A
authors.lastname: Spencer
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D003062:Codon; D016110:Epidermolysis Bullosa Simplex / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D006801:Humans; D007633:Keratins / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree
chemical_list: D003062:Codon; D007633:Keratins