Founder mutations and the high prevalence of myotonia congenita in northern Finland

Objective and Background: To find an explanation at the molecular level for the high prevalence of myotonia congenita in northern Finland and the exce ptional pattern of inheritance of the disease in many families, and to stud y genotype-phenotype correlation in the patients. Methods: Forty-six patien ts with myotonia congenita and 16 unaffected relatives from 24 families wer e studied. All 23 exons and their flanking regions of the gene for the chlo ride channel protein (ClC-1) were sequenced from at least one patient from all families. Results: There were three different mutations of ClC-1 in the patients: one in exon 11, a T-to-G transversion that resulted in the subst itution of cysteine for phenylalanine at amino acid position 413 (F413C); o ne in exon 15, a C-to-T transition that resulted in the substitution of val ine for alanine at amino acid position 531 (A531V); and one in exon 23, a C -to-T transition that resulted in the substitution of a stop codon for an a rginine codon at amino acid position 894 (R894X). Conclusions: Molecular st udies showed that even in families with apparent dominant inheritance, the actual mode of inheritance was autosomal recessive. This was explained not only by the observed consanguinity in some families but by an enrichment of three different mutations of the ClC-1 gene and a consequent high number o f compound heterozygotes in the population. One of the mutations is unique to northern Finland. The conspicuous enrichment of the mutations is likely due to the founder effect and isolation by distance, as in other diseases i n the Finnish heritage.