A novel variant in the CLCN1 gene associated with dominant myotonia congenita reduces the macroscopic chloride conductance and strongly dampens its voltage dependence

We describe a patient presenting the symptoms of myotonia congenita with a new heterozygous missense variant in exon 9 of the CLCN1 gene (c.1010T>G, p.(Phe337Cys)). The mutation is located in the large extracellular loop between the I and J transmembrane segments of CLCN1 and we functionally analyzed its consequences on channel properties. Confocal imaging showed that the F337C mutant incorporated as well as the WT channel into the plasma membrane. Using patch clamp recordings of WT and F337C hClC-1 channels expressed in HEK293 cells, we observed a smaller conductance for the latter at -80 mV. Using classical voltage protocols and curve fitting procedures, we also found a marked reduction of the fast gating component in the mutant channels, as well as an overall reduced voltage-dependence. The mutation did not alter the pharmacology of the channels. Thus the loss of function is due to a reduction of the opening at resting potential and an inability to quickly activate during the action potential and protect the myocytes against repetitive discharges. To our knowledge, this is the first report of a mixed alteration in the biophysical properties of hClC-1 consisting of a reduced conductance at resting potential and an almost abolished voltage dependence.