NOVEL HOMOZYGOUS AND COMPOUND HETEROZYGOUS COL17A1 MUTATIONS ASSOCIATED WITH JUNCTIONAL EPIDERMOLYSIS-BULLOSA

Junctional epidermolysis bullosa is a heritable, heterogeneous blister ing skin disease with mechanically induced dermal-epidermal separation , mild skin atrophy, nail dystrophy, and alopecia. Four unrelated junc tional epidermolysis bullosa families with different phenotypes were i nvestigated here and four novel mutations associated with the disease were identified. Patients 1, 2, and 3 had generalized atrophic benign epidermolysis bullosa, with nonscarring blistering and varying degree of alopecia. Patient 4 had the localisata variant of junctional epider molysis bullosa, with predominantly acral blistering and normal hair. All patients had mutations in the COL17A1 gene encoding collagen XVII, a hemidesmosomal transmembrane protein. Patients 1 and 2 carried homo zygous deletions 520delAG and 2965delG, respectively. Patient 3 was co mpound heterozygous for a missense and a deletion mutation (G539E and 2666delTT), and patient 4 was heterozygous for a known mutation R1226X . The deletions led to premature termination codons and to drastically reduced collagen XVII mRNA and protein levels, consistent with the ab sence of the collagen in generalized atrophic benign epidermolysis bul losa skin, The missense mutation G539E allowed synthesis of immunoreac tive collagen XVII in keratinocytes, but prevented its secretion, thus causing lack of the protein in the skin. The data suggest that differ ent COL17A1 mutations and their combinations can result in a spectrum of biologic and clinical phenotypes of not only generalized atrophic b enign epidermolysis bullosa, but also localized junctional epidermolys is bullosa.