Plectin is a linker-protein that interacts with intermediate filaments and hemidesmosomal proteins, including the beta4 integrin subunit. Mutations in the plectin gene (PLEC) can underlie both autosomal dominant and autosomal recessive (AR) subtypes of the inherited blistering disease, epidermolysis bullosa simplex (EBS). Typically, the mutations in PLEC which cause AR-EBS are nonsense mutations or out‐of‐frame indels. In contrast, pathogenic AR missense mutations in PLEC are rarely observed. Here, we describe two Taiwanese AR-EBS patients with compound heterozygous nonsense/missense PLEC mutations: in both cases the missense mutation is a previously unreported variant, p.Leu319Pro. Both patients had generalized erythematous blistering and erosions, dystrophy of all toe and fingernails, and palmoplantar keratoderma. They did not have obvious muscles weakness, hoarseness, ptosis, or pyloric atresia. Immunofluorescence microscopy of patient skin showed an almost complete absence of plectin labelling. Whole exome sequencing (WES) revealed two heterozygous PLEC mutations, c.6955C>T (p.Arg2319Ter) and c.956T>C (p.Leu319Pro) in case 1, and c.2807G>A (p.Trp936Ter) and c.956T>C (p.Leu319Pro) in case 2. In vitro studies on overexpression of plectin and beta4 integrin revealed significantly reduced plectin in HEK293 transfected with mutant PLEC complementary DNA (cDNA) harboring p.Leu319Pro, than those transfected with wild-type PLEC cDNA. The findings for p.Leu319Pro were similar to those observed for a different reported pathogenic duplication mutation affecting this residue, p.Leu319dup. Our studies highlight the detrimental effect of a missense PLEC mutation on protein stability and extend genotype-phenotype correlation in EBS.

Plectin missense mutation p.Leu319Pro in the pathogenesis of autosomal recessive epidermolysis bullosa simplex