One amino acid deletion in collagen XVII-binding domain of plectin with a truncation mutation underlies epidermolysis bullosa simplex

Abstract

Epidermolysis bullosa simplex (EBS) is a group of congenital skin fragility disorders characterized by intraepidermal skin detachment. PLEC, encoding plectin, is one of the causative genes responsible for EBS. Plectin deficiency is responsible for two autosomal recessive EBS subtypes: EBS with muscular dystrophy (EBS-MD) and EBS with pyloric atresia (EBS-PA). Plectin is a linker protein between hemidesmosomes and intermediate filaments. Plectin harbors a central rod domain which mediates homodimer formation. Plectin transcripts include both full-length and rodless forms. Previous studies indicate that loss of full-length plectin with the maintenance of rodless plectin leads to EBS-MD, whereas both full-length and rodless plectin isoforms are deficient in EBS-PA. However, a few EBS-MD cases have been reported to have in-frame deletions in the N-terminal globular domain of plectin. The Y domain of plectin (Arg618 to Val819) was implicated in binding to collagen XVII (COL17) in yeast two-hybrid assays. However the relevance of plectin-COL17 binding in EBS has not been uncovered. Here, we introduce an EBS patient harboring one amino acid deletion in the N-terminus globular domain (p.Phe755del) and a truncation mutation (p.Leu3065fs) in plectin. Plectin expression in skin specimens and cultured keratinocytes from the patient was diminished at the protein and the mRNA levels. COL17 expression was reduced at the protein level, whereas no pathogenic mutation was detected in the COL17A1 gene. Phe755, a deleted amino acid in one allele of the patient, is located in the Y domain of plectin (Arg618 to Val819). Our study is the first to demonstrate that defects of plectin-COL17 binding might contribute to the EBS phenotype.