Epidermolysis Bullosa: Novel and De Novo Premature Termination Codon and Deletion Mutations in the Plectin Gene Predict Late-Onset Muscular Dystrophy

Abstract

Epidermolysis bullosa (EB) with late-onset muscular dystrophy (EB-MD) is a hemidesmosomal variant of EB due to mutations in the plectin gene (PLEC1). The age of onset of muscle involvement has been noted to vary from infancy to the fourth decade of life. Immunofluorescence of the patients' skin and muscle biopsies is usually negative for staining with antibodies recognizing plectin, a large cytoskeleton-associated anchorage protein. In this study we report novel plectin mutations in two families with EB. In both families, the proband was a newborn with neonatal blistering with no evidence for muscle weakness as yet. Peripheral blood DNA was isolated and examined by heteroduplex scanning strategy, protein truncation test (PTT), and/or direct sequencing of the plectin gene. One of the probands was compound heterozygote for nonsense mutations E2005X/K4460X, and the proband in the second family was compound heterozygote for deletion mutations 5083delG/2745-9del21, the latter mutation extending from -9 to +12 at the intron 22/exon 23 border. The mutations K4460X and 5083delG were not present in either one of the parents, thus being de novo events. In both cases, nonpaternity was excluded by microsatellite marker analysis. The stop codon mutations are predicted to result in the synthesis of a truncated protein lacking the carboxy-terminal globular domain of the protein and possibly causing nonsense-mediated decay of the corresponding mRNA. The 2745-9del21 deletion mutation abolishes the splice site at the intron 22/exon 23 junction, predicting abnormal splicing events. Because plectin deficiency is associated with muscular dystrophy, molecular diagnostics of the plectin gene provides prognostic value in evaluation of these patients who appear to be at risk to develop muscular dystrophy.

Targeted ablation of plectin isoform 1 uncovers role of cytolinker proteins in leukocyte recruitment

“…Patients with recessive mutations suffer from the skin blistering disease epidermolysis bullosa simplex (EBS) combined with late-onset muscular dystrophy (reviewed in ref. 5), whereas a dominant mutation leads to EBS without muscular dystrophy (6). Plectin-deficient mice, die 2-3 days after birth exhibiting severe skin blistering and abnormalities in heart and skeletal muscle (7).…”

Plectin-RACK1 (Receptor for Activated C Kinase 1) Scaffolding

“…1 Several of a series of specific binding partners of plectin identified are constituents of the subplasma membrane protein skeleton or of junctional membrane complexes, such as integrin ␤ 4 , spectrin/ fodrin, and desmoplakin, suggesting that the protein provides a linkage between the cytoskeleton and the cell periphery (1). The crucial role of plectin as a stabilizing element of cells became clearly evident when plectin deficiency due to genetic disorders was found to be the cause for EBS-MD, an autosomal recessive skin blistering disease combined with muscular dystrophy (2), and when a corresponding phenotype was described in plectin knockout mice (3).…”

Epidermolysis bullosa simplex with muscular dystrophy. Review of the literature and a case report

“…It comprises N and C-terminal domains, which contain multiple protein-protein interaction sites, separated by an elongated central rod domain, which is predicted to mediate self-association via coil-coil interactions. 8 In particular, the N-terminal region contains an actin-binding domain (ABD) and a plakin domain, which harbor binding sites for two hemidesmosomal proteins: integrin α6β4 and collagen type XVII. 9,10 The C-terminal region From the analysis of published plectin mutations it is clear, that EBS-MD is usually a result of nonsense, insertion or deletion mutations of exon 31, which encodes for the second rod domain.…”