Pathogenic DST sequence variants result in either epidermolysis bullosa simplex (EBS) or hereditary sensory and autonomic neuropathy type 6 (HSAN‐VI). Issue 6 (19th March 2022)

• Record Type: Journal Article
• Authors: Khalesi, Raziyeh; Harvey, Nailah; Garshasbi, Masoud; Kalamati, Elnaz; Youssefian, Leila; Vahidnezhad, Hassan; Uitto, Jouni
• Is Part Of: Experimental dermatology. Volume 31:Issue 6(2022)
• Page Start: 949
• Page End: 955
• Publication Date: 2022-03-19
• Subjects: bullous pemphigoid antigen‐1 -- DST -- epidermolysis bullosa simplex -- hereditary and sensory autonomic neuropathy type 6; Dermatology -- Periodicals; 616.5
• DOI: 10.1111/exd.14562
• Languages: English
• ISSNs: 0906-6705

Abstract

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 are associated with epidermolysis bullosa simplex (EBS) and hereditary sensory and autonomic neuropathy type 6 (HSAN‐VI). The genotypic spectrum is attested to by 19 distinct mutations but genotype–phenotype correlation for both disorders is not well established. In this study, we performed next‐generation sequencing (NGS) on two families with different phenotypic presentations, one foetus (P1) with musculoskeletal and neurological malformations established by prenatal ultrasound and family history, and a 15‐year‐old female patient (P2) with skin blistering. P1 had a novel homozygous nonsense mutation, DST : NM_001144769, c.3805C>T, p.R1269* within a region of genetic homozygosity (ROH). This mutation resides within the plakin domain of BPAG1 and ablates all isoforms of this protein, leading to novel extracutaneous phenotypes consistent with HSAN‐VI in P1. P2 had 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 in the skin isoform of DST, BPGA1‐e, associated with EBS. In summary, we report two families with pathogenic DST variants and expand the spectrum of DST genotype and phenotypes.