GENETIC-ANALYSIS OF A SEVERE CASE OF DOWLING-MEARA EPIDERMOLYSIS-BULLOSA SIMPLEX

The epidermis serves an important protective function, which it manife sts by producing an extensive cytoskeletal architecture, the unique fe ature of which are keratin filaments. Through studies that began with epidermolysis bullosa simplex (EBS) and now extend to a group of autos omal dominant human blistering skin disorders, it was discovered that defects in the keratin genes lead to cell fragility and degeneration u pon mechanical trauma. In most cases of EBS, point mutations occur in the keratin 5 (K5) and K14 genes expressed in the basal layer of the e pidermis. The precise location of the mutation and the degree to which it causes perturbations in filament assembly correlate with disease s everity. In the present study, we examine a case of EBS, which clinica lly lies at the severe end of the spectrum of Dowling-Meara EBS and wh ich shows keratin filament clumping in suprabasal as well as basal cel ls. We show that one of the two K14 alleles has a single point substit ution, giving rise to a Y129D mutation. This mutation resides 4 residu es internal to the R125C/H hotspot known to account for the majority o f Dowling-Meara cases. We provide functional and structural evidence t o suggest why the Y129D mutation may be capable of creating such a sev ere form of EBS.