Epidermolysis bullosa: Novel and de novo premature termination codon and deletion mutations in the plectin gene predict late-onset muscular dystrophy

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 recognizin g plectin, a large cytoskeleton-associated anchorage protein. In this study we report novel plectin mutations in two families with EB, In both familie s, the proband was a newborn with neonatal blistering with no evidence for muscle weakness as yet. Peripheral blood DNA was isolated and examined by h eteroduplex scanning strategy, protein truncation test (PTT), and/or direct sequencing of the plectin gene, One of the probands was compound heterozyg ote for nonsense mutations E2005X/K4460X, and the proband in the second fam ily was compound heterozygote for deletion mutations 5083delG/2745-9del21, the latter mutation extending from -9 to +12 at the intron 22/exon 23 borde r, The mutations K4460X and 5083delG were not present in either one of the parents, thus being de novo events. Tn both cases, nonpaternity was exclude d by microsatellite marker analysis, The stop codon mutations are predicted to result in the synthesis of a truncated protein lacking the carboxy-term inal globular domain of the protein and possibly causing nonsense-mediated decay of the corresponding mRNA, The 2745-9del21 deletion mutation abolishe s the splice site at the intron 22/exon 23 junction, predicting abnormal sp licing events, Because plectin deficiency is associated with muscular dystr ophy, molecular diagnostics of the plectin gene provides prognostic value i n evaluation of these patients who appear to be at risk to develop muscular dystrophy.