Congenital myasthenic syndrome associated with epidermolysis bullosa caused by homozygous mutations in PLEC1 and CHRNE

Abstract

Mutations in the plectin gene (PLEC1) cause epidermolysis bullosa simplex (EBS), which may associate with muscular dystrophy (EBS-MD) or pyloric atresia (EBS-PA). The association of EBS with congenital myasthenic syndrome (CMS) is also suspected to result from PLEC1 mutations. We report here a consanguineous patient with EBS and CMS for whom mutational analysis of PLEC1 revealed a homozygous 36 nucleotide insertion (1506_1507ins36) that results in a reduced expression of PLEC1 mRNA and plectin in the patient muscle. In addition, mutational analysis of CHRNE revealed a homozygous 1293insG, which is a well-known low-expressor receptor mutation. A skin biopsy revealed signs of EBS, and an anconeus muscle biopsy showed signs of a mild myopathy. Endplate studies showed fragmentation of endplates, postsynaptic simplification, and large collections of thread-like mitochondria. Amplitudes of miniature endplate potentials were diminished, but the endplate quantal content was actually increased. The complex phenotype presented here results from mutations in two separate genes. While the skin manifestations are because of the PLEC1 mutation, footprints of mutations in PLEC1 and CHRNE are present at the neuromuscular junction of the patient indicating that abnormalities in both genes contribute to the CMS phenotype.

Current status of the congenital myasthenic syndromes

“…]). Heteroallelic nonsense, frameshift, or splice-site mutations in PLEC were recently reported in 4 unrelated patients with documented defects in neuromuscular transmission [82–84]. In two patients investigated by the author microelectrode studies of intercostal muscle EPs showed low-amplitude MEPPs.…”

Congenital Myasthenic Syndromes in 2012

“…Pathogenic mutations in plectin result in epidermolysis bullosa simplex, a progressive myopathy and, in some patients, a myasthenic syndrome [52]. Heteroallelic nonsense, frame-shift, or splice-site mutations in PLEC were recently reported in four unrelated patients [2, 53, 54]. In two patients microelectrode studies of intercostal muscle EPs showed low-amplitude MEPPs.…”

“…Morphologic studies revealed dislocated and degenerating muscle fiber organ-elles, plasma membrane defects allowing calcium ingress into the muscle fibers, and degeneration of the junctional folds, all attributable to lack of cytoskeletal support [2]. One patient harbored homozygous frameshift mutations in both PLEC and in CHRNE [54]. …”

Genetic heterogeneity and pathophysiological mechanisms in congenital myasthenic syndromes

“…The kinetic mutations fall into two categories according to whether they induce slow or fast channel syndromes [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] .…”

“…These are the pre-synaptic acetyltransferase CHAT 6 , the gene COLQ 7-8-9 encoding the triple stranded collagenic tail of the synaptic acetylcholinesterase (AChE), the genes encoding the different subunits of the postsynaptic acetylcholine receptors (AChR) CHRNA1, CHRNB1, CHRND, CHRNE and CHRNG, the RAPSN gene encoding the postsynaptic protein rapsyn 10 , the postsynaptic muscle specific kinase (MUSK) gene 11 , the postsynaptic sodium channel (SCN4) 12 , the DOK7 gene encoding the postsynaptic Dok-7 protein [13][14] , the LAMB2 encoding the synaptic Laminin B2 protein 15 , the AGRN gene encoding the postsynaptic agrin protein 16 and the PLEC1 gene encoding the postsynaptic protein plectin. 17-18-19 Genetic classification of the different CMS cohorts reveals that the majority of CMS patients have mutations in genes expressing postsynaptic endplate proteins [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] (table 1). Despite tremendous progress in identifying the molecular basis of the different CMS subtypes, almost half of the CMS population remains genetically undiagnosed.…”