ClC-1 Chloride Channel Mutations in Myotonia Congenita: Variable Penetrance of Mutations Shifting the Voltage Dependence

Abstract

Mutations in the ClC-1 muscle chloride channel cause either recessive or dominant myotonia congenita. Using a systematic screening procedure, we have now identified four novel missense mutations in dominant (V286A, F307S) and recessive myotonia (V236L, G285E), and have analysed the effect of these and other recently described mutations (A313T, I556N) on channel properties in the Xenopus oocyte expression system. Mutations V286A, F307S and A313T displayed a 'classical' dominant phenotype: their voltage dependence was shifted towards positive potentials and displayed a dominant-negative effect by significantly imparting a voltage shift on mutant-wild-type heteromeric channels as found in heterozygous patients. In contrast, the recessive mutation V236L also shifted the voltage dependence to positive values, but co-expression with wild-type ClC-1 gave almost wild-type currents. I556N, a mutation found in patients with benign dominant myotonia, drastically shifts the voltage dependence, but only a slight shift is seen when co-expressed with wild-type ClC-1. Thus, the voltage dependence of mutant heteromeric channels is not always intermediate between those of the constituent homomeric channel subunits, a conclusion further supported by mixing different ClC-1 mutants. These complex interactions correlate clinically with various inheritance patterns, ranging from autosomal dominant with various degrees of penetrance to autosomal recessive.

Difference in allelic expression of the CLCN1 gene and the possible influence on the myotonia congenita phenotype

“…For instance, the F307S mutation was initially found in a dominant family, and electrophysiological characterization supported the dominant nature of the mutation. 14 However, the same mutation has subsequently been found the recessive families. 3 It is quite possible that allelic variation in favor for the mutation is recognized as a dominant phenotype, whereas a shift to the wild-type allele leads to recessive inheritance.…”

“…16 In summary, genomic DNA from the probands was extracted according to standard methods and all 23 exons of CLCN1 were amplified by polymerase chain reaction (PCR) followed by sequencing using intronic primers as described by Kubisch et al 14 Identified mutations were subsequently confirmed in a new PCR and sequencing reaction. The CLCN1 sequence from the two probands, who also volunteered for cDNA analysis, did not show any differences in the primer sites for mRNA analysis.…”

“…14,15 R894X is one of the most common CLCN1 mutations present in many different populations, and is the prime mutation for which both recessive and dominant inheritance has been reported. The mutation is located in the last exon of the CLCN1 gene and leads to a truncation of the terminal 94 amino acids.…”

Myotonia caused by mutations in the muscle chloride channel geneCLCN1

“…Some of the mutations are semidominant (i.e., they are found in recessive as well as dominant pedigrees) (Table 1; Fig. 2) and in some of these cases it has been shown that the shift of the activation curve is either not very big [Kubisch et al, 1998;Zhang et al, 2000a] or is mainly produced by an effect on the single protopore gates [Saviane et al, 1999]. Since the two protopore gates are almost independent of each other (at least once the common gate is open) it is not expected that a modification of one of them has a dominant effect on the whole complex.…”

Myotonia congenita: novel mutations in CLCN1 gene

“…Based on these findings, it is nant mutations. 1,12,14,15,[23][24][25] Furthermore, heterozygotes for the CLCN1 mutation can have a broad phenotypic spectrum, even between heterozygous members of the same family. They can be asymptomatic with mild myotonia revealed only by physical examination in detail.…”