Identification of previously unreported mutations in CHRNA1, CHRNE and RAPSN genes in three unrelated Italian patients with congenital myasthenic syndromes

Abstract

Congenital myasthenic syndromes are rare genetic disorders compromising neuromuscular transmission. The defects are mainly mutations in the muscle acetylcholine receptor, or associated proteins rapsyn and Dok-7. We analyzed three unrelated Italian patients with typical clinical features of congenital myasthenic syndrome, who all benefitted from cholinesterase inhibitors. We found five mutations: a previously unreported homozygous alphaG378D mutation in the CHRNA1 gene, a previously unreported heterozygous epsilonY8X mutation associated with a known heterozygous epsilonM292del deletion in the CHRNE gene, and the common heterozygous N88K mutation associated with a previously unreported heterozygous IVS1 + 2T > G splice site mutation in the RAPSN gene. All three patients had two mutant alleles; parents or offspring with a single mutated allele were asymptomatic, thus all mutations exerted their effects recessively. The previously unreported mutations are likely to reduce the number of AChRs at the motor endplate, although the alphaG378D mutation might produce a mild fast channel syndrome. The alphaG378D mutation was recessive, but recessive CHRNA1 mutations have rarely been reported previously, so studies on the effect of this mutation at the cellular level would be of interest.

Congenital myasthenic syndromes

“…Mutations in CHRNA1 result in imbalance between the two splice variants with an increase in P3A+. CHRNA1 mutations reduce the number of AchR at the post-synaptic membrane [54]. The pattern of inheritance is AD if CHRNA1 mutations cause a slow channel CMS (SCCMS) or AR in case of primary AchR-deficiency [54].…”

“…CHRNA1 mutations reduce the number of AchR at the post-synaptic membrane [54]. The pattern of inheritance is AD if CHRNA1 mutations cause a slow channel CMS (SCCMS) or AR in case of primary AchR-deficiency [54]. The first CHRNA1 -related CMS were reported in 2008 [54] (Table 1).…”

Neuromuscular disorders and 2010: recent advances

“…The mutational spectrum of the CHRNA1, CHRNE and RAPSN genes was further expanded by the identification of three novel variants in three unrelated Italian CMS patients [5]. The clinical features of the patients are similar to previous reports, and all patients benefited from treatment with cholinesterase inhibitors.…”

A novel mutation in the TPR6 domain of the RAPSN gene associated with congenital myasthenic syndrome

“…RAPSN mutations lead to severely reduced AChR numbers and density at the endplate and a loss of postsynaptic folds. Although more than 30 mutations in the RAPSN gene have been described, the N88K mutation is the most common accounting for about 90% of affected individuals of European origin, either as homozygous or as a compound heterozygous [3][4][5]. E box mutations have been identified in the promoter region.…”

“…RFLP analysis for detecting the p.224 insT mutation in mother[1], father[2] and patients[3,4]. (M)-100 bp DNA ladder.…”