Common founder effect of rapsyn N88K studied using intragenic markers

Abstract

Mutations in the human gene encoding rapsyn have been linked to a recessive form of postsynaptic congenital myasthenic syndrome due to deficient clustering of acetylcholine receptors at the endplate. All patients reported to date carry the N88K mutation, suggesting a possible common founder effect. To decrease the likelihood of a recombination event occurring within the span of neighboring microsatellite markers, we used seven intragenic single nucleotide polymorphisms (SNPs) spanning 8 kb to characterize the haplotype associated with N88K. In three affected N88K homozygous individuals, we identified a common haplotype present in all heterozygous carriers of N88K. Of note, in two asymptomatic N88K homozygous individuals, a second haplotype was present that differed at three SNP sites downstream from the N88K mutation. Our findings of a common haplotype associated with the N88K mutation support a founder effect. The discordant haplotype found in homozygous individuals suggests that recombination events may have occurred within the rapsyn gene and that this may have implications in the phenotypic expression of the disease.

Investigation for RAPSN and DOK‐7 mutations in a cohort of seronegative myasthenia gravis patients

“…Thus, the number of N88K homozygotes in the Norwegian population should be 400 (1 per 12,000). However, the high carrier frequency of the N88K mutation has not been borne out in other studies,9, 20, 21 and thus the estimated number of N88K homozygotes is likely too high. In the region served by Haukeland University Hospital (population 1 million) there are 5 patients with a diagnosis of CMS (ICD‐10: G70.2).…”

Congenital myasthenic syndromes: spotlight on genetic defects of neuromuscular transmission

“…All RAPSN mutations described so far show a recessive inheritance pattern, although in the case of N88K – given its relatively high frequency – pseudodominant inheritance is possible (Ref. 62).…”

Interleukin-10 promoter polymorphisms in myasthenia gravis

“…This estimated homozygote frequency suggests that the number of N88K homozygotes in the Norwegian population (4.8 million) is about 380. However, such a high carrier frequency of the N88K mutation has not been found in other studies [160,162,190]. The estimated number of N88K homozygotes may therefore be too high.…”