Functional characterization of ClC-1 mutations from patients affected by recessive myotonia congenita presenting with different clinical phenotypes.
Myotonia congenita (MC) is caused by loss-of-function mutations of the muscle ClC-1 chloride channel. Clinical manifestations include the variable association of myotonia and transitory weakness. We recently described a cohort of recessive MC patients showing, at a low rate repetitive nerves stimulation protocol, different values of compound muscle action potential (CMAP) transitory depression, which is considered the neurophysiologic counterpart of transitory weakness. From among this cohort, we studied the chloride currents generated by G190S (associated with pronounced transitory depression), F167L (little or no transitory depression), and A531V (variable transitory depression) hClC-1 mutants in transfected HEK293 cells using patch-clamp. While F167L had no effect on chloride currents, G190S dramatically shifts the voltage dependence of channel activation and A531V reduces channel expression. Such variability in molecular mechanisms observed in the hClC-1 mutants may help to explain the different clinical and neurophysiologic manifestations of each ClCN1 mutation. In addition we examined five different mutations found in compound heterozygosis with F167L, including the novel P558S, and we identified additional molecular defects. Finally, the G190S mutation appeared to impair acetazolamide effects on chloride currents in vitro.
Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari-Aldo Moro, Bari, Italy. Electronic address: jfdesaphy@farmbiol.uniba.it.
Jean-François
JF
Desaphy
Gianluca
G
Gramegna
Concetta
C
Altamura
Maria Maddalena
MM
Dinardo
Paola
P
Imbrici
Alfred L
AL
George
Anna
A
Modoni
Mauro
M
Lomonaco
Diana
D
Conte Camerino
D000200:Action Potentials / Q000502:physiology; D018118:Chloride Channels / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D018482:Muscle, Skeletal / Q000378:metabolism / Q000503:physiopathology; D009154:Mutation; D009224:Myotonia Congenita / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D010641:Phenotype
C086321:CLC-1 channel; D018118:Chloride Channels
Acetazolamide; Chloride channel mutation; ClC-1 chloride channel; Genotype–phenotype relationship; Myotonia congenita; Non-dystrophic myotonia; Patch-clamp; Transitory weakness