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Neurology. 2000 Feb 22;54(4):937-42.

Functional consequences of chloride channel gene (CLCN1) mutations causing myotonia congenita.

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1
Department of Neurology, University of Utah, Salt Lake City 84112-5331, USA.

Abstract

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.

PMID:
10690989
[Indexed for MEDLINE]
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