Pathogenic DST sequence variants result in either epidermolysis bullosa simplex (EBS) or hereditary sensory and autonomic neuropathy type 6 (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 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.

DST variants are responsible for neurogenic arthrogryposis multiplex congenita enlarging the spectrum of type VI hereditary sensory autonomic neuropathy

“…Biallelic variants in the neuronal isoforms cause HSAN6 (MIM: 614653) which has been reported in several unrelated families with highly variable phenotypes (Table 1). 6–20 HSAN6 was initially described in a family of four affected individuals who presented with severe dysautonomic symptoms, distal contractures, severe psychomotor retardation, and early death 8 . The motor phenotype of the affected fetus reported here is similar to the affected individuals reported by Edvardson et al More recently, HSAN6 was reported as associated with congenital contractures 9,10 .…”

“…HSAN6 was initially described in a family of four affected individuals who presented with severe dysautonomic symptoms, distal contractures, severe psychomotor retardation, and early death 8. The motor phenotype of the affected fetus reported here is similar to the affected individuals reported by Edvardson et al More recently, HSAN6 was reported as associated with congenital contractures 9,10. The positions of DST variants in the cases associated with congenital contractures are not restricted to a specific domain of the DST protein (tion.…”

“…) [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. HSAN6 was initially described in a family of four affected individuals who presented with severe dysautonomic symptoms, distal contractures, severe psychomotor retardation, and early death 8.…”

Mutation update: The spectra of PLEC sequence variants and related plectinopathies

“…To date, 16 genes involved in dermal‐epidermal integrity and adhesion have been linked to the pathogenesis of different classic forms of EB. In EBS alone, seven genes have currently been identified as candidate genes: KRT5, KRT14, CD151, KLHL24, DST, EXPH5 , and PLEC (Has et al, 2020; Khalesi et al, 2022; Vahidnezhad et al, 2016; Vahidnezhad, Youssefian, Daneshpazhooh, et al, 2019; Vahidnezhad, Youssefian, Saeidian, Mahmoudi, et al, 2018; Vahidnezhad, Youssefian, Saeidian, Touati, et al, 2018).…”

Hypolacrimia and Alacrimia as Diagnostic Features for Genetic or Congenital Conditions

“…It is speculated that the truncation of pathogenic variations that result in the loss of expression of all neuronal isoforms produces a severe disorder with congenital defects and early lethality, whereas pathogenic variation combinations that partially maintain dystonin protein expression and function will have less severe clinical expression and will generate neuropathies without major reduction of lifespan. 87 , 88 In vitro studies have shown that dystonin is significantly more abundant in cells of familial dysautonomia patients bearing IKBKAP pathogenic variations in comparison with control fibroblasts. 81 This suggests that upregulation of dystonin could be an adaptive cellular response in HSAN3 patients.…”