A large cohort of myotonia congenita probands: novel mutations and a high-frequency mutation region in exons 4 and 5 of the CLCN1 gene

作者：Brugnoni Raffaella; Kapetis Dimos; Imbrici Paola; Pessia Mauro; Canioni Eleonora; Colleoni Lara; de Ro**o Nicole Kerlero; Morandi Lucia; Cudia Paola; Gashemi Nasrin; Bernasconi Pia^*; Desaphy Jean Francois; Conte Diana; Mantegazza Renato

来源：Journal of Human Genetics, 2013, 58(9): 581-587.

DOI：10.1038/jhg.2013.58

• CLCN1 gene
• genetic screening
• myotonia congenita
• skeletal muscle voltage-gated chloride channel (ClC-1)

Myotonia congenita is a genetic disease characterized by impaired muscle relaxation after forceful contraction (myotonia) and caused by mutations in the chloride channel voltage-sensitive 1 (CLCN1) gene, encoding the voltage-gated chloride channel of skeletal muscle (ClC-1). In a large cohort of clinically diagnosed unrelated probands, we identified 75 different CLCN1 mutations in 106 individuals, among which 29 were novel mutations and 46 had already been reported. Despite the newly described mutations being scattered throughout the gene, in our patients, mutations were mostly found in exons 4 and 5. Most of the novel mutations located in the region comprising the intramembrane helices are involved in the ion-conducting pathway and predicted to affect channel function. We report for the first time that two mutations, inherited on the same allele as a heterozygous trait, abrogate disease expression, although when inherited singularly they were pathogenic. Such a mode of inheritance might explain the incomplete penetrance reported for autosomal dominant mutations in particular families.

• 出版日期2013-9