CLC-1 CHLORIDE CHANNEL MUTATIONS IN MYOTONIA-CONGENITA - VARIABLE PENETRANCE OF MUTATIONS SHIFTING THE VOLTAGE-DEPENDENCE

Mutations in the CIC-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 (V2 86A, F307S) and recessive myotonia (V236L, G285E), and have analysed t he effect of these and other recently described mutations (A313T, I556 N) on channel properties in the Xenopus oocyte expression system. Muta tions V286A, F307S and A313T displayed a 'classical' dominant phenotyp e: their voltage dependence was shifted towards positive potentials an d displayed a dominant-negative effect by significantly imparting a vo ltage shift on mutant-wild-type heteromeric channels as found in heter ozygous patients. In contrast, the recessive mutation V236L also shift ed the voltage dependence to positive values, but coexpression with wi ld-type CIC-1 gave almost wild-type currents. I556N, a mutation found in patients with benign dominant myotonia, drastically shifts the volt age dependence, but only a slight shift is seen when co-expressed with wild-type CIC-1, Thus, the voltage dependence of mutant heteromeric c hannels is not always intermediate between those of the constituent ho momeric channel subunits, a conclusion further supported by mixing dif ferent CIC-1 mutants. These complex interactions correlate clinically with various inheritance patterns, ranging from autosomal dominant wit h various degrees of penetrance to autosomal recessive.