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CACNA1A mutations causing episodic and progressive ataxia alter channel trafficking and kinetics

From the Departments of Neurology (Drs. Wan, Jen, and Baloh, and M. Sandusky) and Physiology (Drs. Khanna and Papazian), University of California at Los Angeles. R. Khanna is currently affiliated with the Division of Cellular and Molecular Biology, Toronto Western Research Institute, Canada.

Address correspondence and reprint requests to Dr. Wan, Department of Neurology, University of California at Los Angeles, 710 Westwood Plaza, Los Angeles, CA 90095-1769; e-mail: jjwan{at}ucla.edu

Background: CACNA1A encodes Ca_V2.1, the pore-forming subunit of P/Q-type voltage-gated calcium channel complexes. Mutations in CACNA1A cause a wide range of neurologic disturbances variably associated with cerebellar degeneration. Functional studies to date focus on electrophysiologic defects that do not adequately explain the phenotypic findings.

Objective: To investigate whether some missense mutations might interfere with protein folding and trafficking, eventually leading to protein aggregation and neuronal injury.

Methods: The authors studied the functional consequences of two pore missense mutations, C287Y and G293R, in two families with EA2, one newly discovered and the other previously reported. Both mutations caused episodic and interictal ataxia. The biophysical properties of mutant and wild type calcium channels were examined by whole-cell patch-clamp recordings in transfected COS-7 cells. The plasma membrane targeting was visualized by confocal fluorescence imaging on Ca_V2.1 tagged with green fluorescent protein.

Results: The mutant channels exhibited a marked reduction in current expression and deficiencies in plasma membrane targeting.

Conclusions: In addition to altered channel function, the deficiency in protein misfolding and trafficking associated with the C287Y and G293R mutants may contribute to the slowly progressive cerebellar ataxia.

Supported by Osserman/Sosin/McClure Fellowship from Myasthenia Gravis Foundation of America, Inc. (J.W.), NIH grants NIDCD P50 DC05524 (R.W.B.) and NIDCD K23 DC00162 (J.J.), and departmental support from UCLA Neurology.

Received October 20, 2004. Accepted in final form March 14, 2005.

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