Myotonia congenita in a large consanguineous Arab family: Insight into the clinical spectrum of carriers and double heterozygotes of a novel mutation in the chloride channel CLCN1 gene

Abstract

The aims of this study were to (1) characterize the clinical phenotype, (2) define the causative mutation, and (3) correlate the clinical phenotype with genotype in a large consanguineous Arab family with myotonia congenita. Twenty-four family members from three generations were interviewed and examined. Genomic DNA was extracted from peripheral blood samples for sequencing the exons of the CLCN1 gene. Twelve individuals with myotonia congenita transmitted the condition in an autosomal dominant manner with incomplete penetrance. A novel missense mutation [568GG>TC (G190S)] was found in a dose-dependent clinical phenotype. Although heterozygous individuals were asymptomatic or mildly affected, the homozygous individuals were severely affected. The mutation is a glycine-to-serine residue substitution in a well-conserved motif in helix D of the CLC-1 chloride channel in the skeletal muscle plasmalemma. A novel mutation, 568GG>TC (G190S) in the CLCN1 gene, is responsible for autosomal dominant myotonia congenita with a variable phenotypic spectrum.

Novel brain expression of ClC-1 chloride channels and enrichment of CLCN1 variants in epilepsy

“…or allelic variation that favors increased variant mRNA level correlates with a more severe pathology. 27,[30][31][32] Heteromeric subunit complexity may also account for the uncommon co-occurrence of clinical epilepsy in human myotonia. There is widespread overlap of CLCN1-3 regional expression in brain networks.…”

Myotonia congenita: Novel mutations in CLCN1 gene and functional characterizations in Italian patients

“…This mutation was first described in a large consanguineous Arab family [10] in both heterozygous and homozygous forms. It is sited on exon 5, which falls in the D-domain and it implies a neutral side chain to turn into a polar one.…”

“…Furthermore the following mutations found in eight patients were considered for functional analysis: p.Trp164Arg, p.Ile197Arg and p.Gly845Ser, together with the previously reported p.Gly190Ser [10] which was present in 5 patients from our cohort. All the tested mutations, with the exception of p.Gly845Ser, caused alterations in the functional characteristics of hClC-1 channels, which consisted in modifications in the voltage-dependence of open probability, in the deactivating behavior and in pore properties.…”

Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease

“…This would seem to be especially true in the context of low-penetrance mutations such as those identified in the SCN4A and CLCN1 genes, causing muscle channelopathies, conditions which are usually held to be transmitted in an autosomal dominant fashion. Patients homozygous for sodium channel mutations causing paramyotonia congenita ( SCN4A , Ile1393Thr), hypokalemic periodic paralysis ( SCN4A , Arg1132Gln) and myotonia congenita ( CLCN1 , Gly190Ser, Ile556Asn, Ala313Thr, Ile556Asn) display much more severe clinical features than patients heterozygous for these mutations (Plassart-Schiess et al 1998; Arzel-Hézode et al 2010; Shalata et al 2010). The aforementioned mutations were also found to exhibit reduced penetrance in heterozygotes.…”