Congenital Myasthenic Syndrome (CMS) in Three European Kinships due to a Novel Splice Mutation (IVS7 - 2 A/G) in the Epsilon Acetylcholine Receptor (AChR) Subunit Gene

Abstract

Mutations in the epsilon-acetylcholine receptor (AChR epsilon) subunit gene cause congenital myasthenic syndromes (CMS) with postsynaptic neural transmission defects. We present 3 male and 2 female patients from three unrelated Croatian, Hungarian, and Russian families with autosomal recessive CMS. All patients manifested with variable degrees of ophthalmoparesis and generalized, fatiguable muscle weakness since birth or early infancy. Electrophysiological studies showed a decremental response in all patients indicating a neuromuscular transmission defect. Pyridostigmine treatment improved the proximal muscle weakness whereas the ophthalmoparesis remained unchanged in all patients. Analysis of the AChR epsilon subunit gene showed homozygosity for a novel splice site mutation of intron 7 epsilon(IVS7-2A/G) in the two Croatian siblings. epsilon-mRNA analysis by RT-PCR and direct sequencing revealed that exon 7 was spliced directly to exon 9 with skipping of exon 8. The Hungarian and Russian patients were heteroallelic carriers of the same mutation epsilon(IVS7-2A/G) and of a frameshifting mutation epsilon 70insG and epsilon 1293insG, respectively. We hypothesize that altered splice products may not be expressed as functional receptors at the cell surface. A haplotype analysis with polymorphic markers revealed a high degree of similarity for the epsilon(IVS7-2A/G) carrying allele in all families and may therefore indicate a common origin of the mutation.

A common CHRNE mutation in Brazilian patients with congenital myasthenic syndrome

“…Careful selection of patients with a few simple clinical features can lead to a percentage as high as 72.2% of patients with the mutation, which could be a useful tool for the first screening of CMS patients, including in different countries where other CHRNE mutations also have a founder effect. Main clinical data from patients with the CHRNE c.130dupG mutation + = present; -= absent; nd = no data or not tested; EO = early onset; IP = improvement with pyridostigmine; FS = fluctuating symptoms; IEM = imparied eye movement; PIE = partially impaired eye movement; SRI= impaired eye movement sparing rectus inferior muscles; PP = ptosis; LW = limb weakness; BS = bulbar symptoms; FI = facial involvement; NPC = no progressive course; Variants found associated with c.130dupG: c.803-2A>G (previously reported as pathogenic [11]); c.858_859dup (p.leu287ser fs*14, novel); c.422T>A (p.pro141.leu, previously reported as pathogenic [12]).…”

Spectrum of splicing errors caused by CHRNE mutations affecting introns and intron/exon boundaries

“…Three other splicing mutations had been previously characterised. [2][3][4] To summarise, exons 5, 6, 8, 9, and 10 are skipped, and introns 7, 9, and 11 are retained. The three retained introns are all short (intron 7, 82 bp; intron 9, 83 bp; and intron 11, 109 bp), whereas four of five skipped exons flank medium to long introns on either or both sides (exon 5 is flanked by 129 and 306 bp introns; exon 6 by 306 and 334 bp introns; exon 8 by 82 and 1210 bp introns; and exon 9 by 1210 and 83 bp introns).…”

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

“…One of the most common types of CMS is congenital AChR deficiency, which often results from mutations in CHRNE. A single CHRNE mutation, 1293insG, has been encountered in patients from America (12), eastern Europe (13), and North Africa (14), and it has been suggested that it may derive from a common founder.…”