Functional consequences of chloride channel gene (CLCN1) mutations causing myotonia congenita.
OBJECTIVE
To determine the functional consequences of missense mutations within the skeletal muscle chloride channel gene CLCN1 that cause myotonia congenita.


BACKGROUND
Myotonia congenita is a genetic muscle disease associated with abnormalities in the skeletal muscle voltage-gated chloride (ClC-1) channel. In order to understand the molecular basis of this inherited disease, it is important to determine the physiologic consequences of mutations found in patients affected by it.


METHODS
The authors used a mammalian cell (human embryonic kidney 293) expression system and the whole-cell voltage-clamp technique to functionally express and physiologically characterize five CLCN1 mutations.


RESULTS
The I329T mutation shifted the voltage dependence of open probability of ClC-1 channels to the right by 192 mV, and the R338Q mutation shifted it to the right by 38 mV. In addition, the I329T ClC-1 channels deactivated to a lesser extent than normal at negative potentials. The V165G, F167L, and F413C ClC-1 channels also shifted the voltage dependence of open probability, but only by +14 to +20 mV.


CONCLUSIONS
The functional consequences of these mutations form the physiologic argument that these are disease-causing mutations and could lead to myotonia congenita by impairing the ability of the skeletal muscle voltage-gated chloride channels to maintain normal muscle excitability. Understanding of genetic and physiologic defects may ultimately lead to better diagnosis and treatment of patients with myotonia congenita.
Zhang
J
J
Department of Neurology, University of Utah, Salt Lake City 84112-5331, USA.
Bendahhou
S
S
Sanguinetti
M C
MC
Ptácek
L J
LJ
D018118:Chloride Channels / Q000235:genetics* / Q000502:physiology; D006801:Humans; D020125:Mutation, Missense / Q000235:genetics; D009224:Myotonia Congenita / Q000209:etiology* / Q000235:genetics* / Q000503:physiopathology
C086321:CLC-1 channel; D018118:Chloride Channels