Epidermolysis bullosa simplex mit Mutation in Plectin-Isoform 1a Q82.8

Gostyńska KB et al. 2015

Epidermolysis bullosa simplex (EBS) with mutation in plectin isoform 1a (see notes below) is characterized by initially localized later also generalized bullous epidermolysis. Dystrophy of the fingernails and toenails. No mucosal involvement (Gostyńska KB et al. 2015).

It begins at running age with blisters on the feet and may generalize by puberty, sparing the mucous membranes in cases observed to date (Gostyńska KB et al. 2015). Hyperkeratotic papules and a mild form of palmoplantar keratosis are also observed. The skin lesions heal with scarring and hyperpigmentation. Scalp, axillary and pubic hair are normal. There was no evidence of enamel disorders.

There was no evidence of cardiomyopathies or muscular dystrophies in this PLEC variant of EBS.

Homozygous nonsense mutation (c.46C>T; p.Arg16X) in the first exon of the plectin variant encoding plectin isoform 1a (P1a).

Controls revealed that P1a was not expressed by myocytes in striated muscle and myocardium, whereas the common plectin epitope (10F6) is detectable in Z-disks of striated muscle and intercalation disks of myocardium. In contrast, P1a is expressed along the basement membrane of the oral cavity mucosa and to a limited extent in the conjunctiva.

Animal experiments have shown that plectin 1a is proteolytically degraded in contrast to plectin 1c, the major isoform expressed in epidermal keratinocytes, supporting the notion that degradation of hemidesmosome-anchored plectin is spatially controlled. Using recombinant proteins, it was shown that mutation renders the 190 nm coiled-coil rod domain of plectin more susceptible to cleavage by calpains and other proteases activated in epidermis but not in skeletal muscle (Walko G et al. 2011).

The dominant expression of the P1a isoform in the epidermal basal cell layer and in cultured keratinocytes suggests that mutations in the first exon of isoform 1a exclusively cause EBS in skin without extracutaneous involvement.

Epidermolysis bullosa simplex (EBS) with mutation in plectin isoform 1a (see notes below) is characterized by initially localized later also generalized bullous epidermolysis. Dystrophy of the fingernails and toenails. No mucosal involvement (Gostyńska KB et al. 2015).

It begins at running age with blisters on the feet and may generalize by puberty, sparing the mucous membranes in cases observed to date (Gostyńska KB et al. 2015). Hyperkeratotic papules and a mild form of palmoplantar keratosis are also observed. The skin lesions heal with scarring and hyperpigmentation. Scalp, axillary and pubic hair are normal. There was no evidence of enamel disorders.

There was no evidence of cardiomyopathies or muscular dystrophies in this PLEC variant of EBS.

EM: Electron microscopy revealed hypoplastic hemidesmosomes and intraepidermal pseudofunctional cleavage, with the plasma membrane of basal cells visible on the blister floor.

The PLEC gene encodes the cytolinker protein plectin, which is ubiquitously found in skin, mucosa, intestine, muscle and heart tissue. PLEC has eight tissue-specific isoforms in humans that result from alternative splicing of the first exon. To date, all PLEC mutations causing epidermolysis bullosa simplex (EBS) have been found in exons common to all isoforms. As a consequence, due to the ubiquitous occurrence of plectin in mammalian tissues, all phenotypes associated with PLEC mutations are linked by mucocutaneous blistering, muscular dystrophy, pyloric atresia, and/or cardiomyopathy (Winter L et al. 2013; Charlesworth A et al. 2013).

1. Charlesworth A et al (2013) Epidermolysis bullosa simplex with PLEC mutations: new phenotypes and new mutations. Br J Dermatol 168: 808-814.
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3. Gostyńska KB et al (2015) Mutation in exon 1a of PLEC, leading to disruption of plectin isoform 1a, causes autosomal-recessive skin-only epidermolysis bullosa simplex. Hum Mol Genet 24:3155-3162.
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