Mutation in exon 1a of PLEC, leading to disruption of plectin isoform 1a, causes autosomal-recessive skin-only epidermolysis bullosa simplex.

Abstract

PLEC, the gene encoding the cytolinker protein plectin, has eight tissue-specific isoforms in humans, arising by alternate splicing of the first exon. To date, all PLEC mutations that cause epidermolysis bullosa simplex (EBS) were found in exons common to all isoforms. Due to the ubiquitous presence of plectin in mammalian tissues, EBS from recessive plectin mutations is always associated with extracutaneous involvement including muscular dystrophy, pyloric atresia and cardiomyopathy. We studied a consanguineous family with sisters having isolated blistering suggesting EBS. Skin disease started with foot blisters at walking age and became generalized at puberty while sparing mucous membranes. DNA sequencing revealed a homozygous nonsense mutation (c.46C>T; p.Arg16X) in the first exon of the plectin variant encoding plectin isoform 1a (P1a). Immunofluorescence antigen mapping, transmission electron microscopy, western blot analysis and qRT-PCR were performed on patient skin and cultured keratinocytes, control myocardium and striated muscle samples. We found hypoplastic hemidesmosomes and intra-epidermal 'pseudo-junctional' cleavage fitting EBS. Screening for cardiomyopathy and muscle dystrophy showed no abnormalities. We report the first cases of autosomal-recessive EBS from P1a deficiency affecting skin, while mucous membranes, heart and muscle are spared. The dominant expression of the P1a isoform in epidermal basal cell layer and cultured keratinocytes suggests that mutations in the first exon of isoform 1a cause skin-only EBS without extracutaneous involvement. Our study characterizes yet another of the eight isoforms of plectin and adds a tissue-specific phenotype to the spectrum of 'plectinopathies' produced by mutations of unique first exons of this gene.

• Authors: Katarzyna B Gostyńska, Miranda Nijenhuis, Henny Lemmink, Hendri H Pas, Anna M G Pasmooij, Kristin Kernland Lang, Maria J Castañón, Gerhard Wiche, Marcel F Jonkman
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 24 Issue 11 Pg. 3155-62 (Jun 01 2015) ISSN: 1460-2083 [Electronic] England
• PMID: 25712130 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• PLEC protein, human
• Plectin

Topics

• Adult
• Amino Acid Sequence
• Base Sequence
• Cells, Cultured
• Consanguinity
• DNA Mutational Analysis
• Epidermolysis Bullosa Simplex (genetics, metabolism)
• Exons
• Female
• Genetic Association Studies
• Humans
• Molecular Sequence Data
• Pedigree
• Plectin (genetics, metabolism)