495 Mutations in different domains of bullous pemphigoid antigen-1 (BPGA1) encoded by DST result in either epidermolysis bullosa simplex or musculoskeletal and neuronal deformities-associated HSAN-VI

Abstract

DST encodes bullous pemphigoid antigen-1 (BPAG1), a protein with eight tissue-specific isoforms expressed in the skin, muscle, brain, and nerves. Accordingly, mutations in this gene cause different phenotypes, including epidermolysis bullosa simplex (EBS) and hereditary sensory and autonomic neuropathy type VI (HSAN-VI). The genotype-phenotype correlation is attested to by 19 distinct mutations but not well established for both disorders. In this study, we performed next-generation sequencing (NGS) on two families with different phenotypic presentations, one fetus (P1) with musculoskeletal and neurological malformations established by prenatal ultrasound and family history, and a 15-year-old female (P2) with skin blistering. P1 had a novel homozygous nonsense mutation, DST: NM_001144769, c.3805C>T, p.R1269* within a region of homozygosity (ROH). This mutation, within the plakin domain, ablates all BPGA1 isoforms leading to novel extracutaneous phenotypes in P1. P2 has a recurrent homozygous mutation DST: NM_001723.7, c.3370C>T, p.Gln1124* that presented with giant, trauma-induced skin blisters without extracutaneous involvement. This mutation is located within the coiled-coil domain present on the skin isoform of DST, BPGA1-e, associated with EBS. In summary, we report two Iranian families with DST variants, expanding the genotypic and phenotypic spectrum of DST.