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Functional implications of a novel EA2 mutation in the P/Q‐type calcium channel
Author(s) -
Spacey Sian D.,
Hildebrand Michael E.,
Materek Luke A.,
Bird Thomas D.,
Snutch Terrance P.
Publication year - 2004
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.20169
Subject(s) - missense mutation , mutation , calcium channel , acetazolamide , ataxia , wild type , voltage dependent calcium channel , chemistry , gene , genetics , medicine , calcium , neuroscience , biology , biochemistry , mutant
Episodic ataxia type 2 (EA2) is an autosomal dominant condition characterized by paroxysmal attacks of ataxia, vertigo, and nausea, typically lasting minutes to days in duration. These symptoms can be prevented or significantly attenuated by the oral administration of acetazolamide; however, the mechanism by which acetazolamide ameliorates EA2 symptoms is unknown. EA2 typically results from nonsense mutations in the CACNA1A gene that encodes the α 1A (Ca v 2.1) subunit of the P/Q‐type calcium (Ca 2+ ) channel. We have identified a novel H1736L missense mutation in the CACNA1A gene associated with the EA2 phenotype. This mutation is localized near the pore‐forming region of the P/Q‐type Ca 2+ channel. Functional analysis of P/Q‐type channels containing the mutation show that the H1736L alteration affects several channel properties, including reduced current density, increased rate of inactivation, and a shift in the voltage dependence of activation to more positive values. Although these findings are consistent with an overall loss of P/Q‐type channel function, the mutation also caused some biophysical changes consistent with a gain of function. We also tested the direct effect of acetazolamide on both wild‐type and H1736L mutated P/Q‐type channels and did not observe any direct action on channel properties of this pharmacological agent used to treat EA2 patients. Ann Neurol 2004