Compound heterozygosity for novel splice site mutations in the BPAG2/COL17A1 gene underlies generalized atrophic benign epidermolysis bullosa

Generalized atrophic benign epidermolysis bullosa, GABEB (OMIM# 226650), is a nonlethal variant of epidermolysis bullosa with autosomal recessive inhe ritance pattern. The pathogenesis of this disorder can be caused by mutatio ns affecting two different gene/protein systems. Most of the mutations have been identified in the BPAG2/COL17A1 gene encoding a hemidesmosomal transm embrane protein,the 180 kDa bullous pemphigoid antigen (BP180), also known as type XVII collagen. The minority of the mutations are localized in the L AMB3 gene encoding the beta 3 polypeptide of laminin 5. In this study we de scribe a GABEB patient who showed absent expression of BP180 in the culture d keratinocytes as well as in the skin. The patient was a compound heterozy gote for two different splice site mutations, 3053-1G-->C and 3871+1G-->C, affecting the extracellular domain of the protein. These mutations resulted in multiple aberrant splice variants, three of them causing premature term ination codons for translation, This case, dealing with out-of-frame splice site mutations in BPAG2/COL17A1, attests to the molecular heterogeneity of GABEB.