Document Detail

Genetic and functional characterisation of the P/Q calcium channel in episodic ataxia with epilepsy.
MedLine Citation:
PMID:  20156848     Owner:  NLM     Status:  MEDLINE    
Mutations in CACNA1A, which encodes the principal subunit of the P/Q calcium channel, underlie episodic ataxia type 2 (EA2). In addition, some patients with episodic ataxia complicated by epilepsy have been shown to harbour CACNA1A mutations, raising the possibility that P/Q channel dysfunction may be linked to human epilepsy. We undertook a review of all published CACNA1A EA2 cases and this showed that 7% have epilepsy--representing a sevenfold increased epilepsy risk compared to the background population risk (P<0.001). We also studied a series of 17 individuals with episodic ataxia accompanied by epilepsy and/or clearly epileptiform electroencephalograms (EEGs). We screened the entire coding region of CACNA1A for point mutations and rearrangements to determine if genetic variation in the gene is associated with the epilepsy phenotype, and measured the functional impact of all missense variations on heterologously expressed P/Q channels. We identified two large scale deletions and two new missense mutations in CACNA1A. When expressed, L621R had little detectable effect on P/Q channel function, while the other missense change, G540R, caused an approximately 30% reduction in current density. In nine patients we also identified the previously reported non-synonymous coding variants (E921D and E993V) which also resulted in impairment of P/Q channel function. Taken together, 12 of the 17 patients have genetic changes which decrease P/Q channel function. We conclude that variants in the coding region of CACNA1A that confer a loss of P/Q-type channel function are associated with episodic ataxia and epilepsy. Our data suggest that functional stratification of all variants, including common polymorphisms, rare variants and novel mutations, may provide new insights into the mechanisms of channelopathies.
Sanjeev Rajakulendran; Tracey D Graves; Robyn W Labrum; Dimitrios Kotzadimitriou; Louise Eunson; Mary B Davis; Rosalyn Davies; Nicholas W Wood; Dimitri M Kullmann; Michael G Hanna; Stephanie Schorge
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-02-15
Journal Detail:
Title:  The Journal of physiology     Volume:  588     ISSN:  1469-7793     ISO Abbreviation:  J. Physiol. (Lond.)     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-06-02     Completed Date:  2010-08-27     Revised Date:  2014-02-24    
Medline Journal Info:
Nlm Unique ID:  0266262     Medline TA:  J Physiol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1905-13     Citation Subset:  IM    
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MeSH Terms
Ataxia / complications,  genetics*,  physiopathology*
Calcium Channels / genetics*,  physiology
Cell Line
Child, Preschool
DNA / genetics
Epilepsy / complications,  genetics*,  physiopathology*
Middle Aged
Mutation / genetics
Mutation, Missense / genetics
Patch-Clamp Techniques
Point Mutation / genetics,  physiology
Polymorphism, Single Nucleotide
Young Adult
Grant Support
084655//Wellcome Trust; G0601943//Medical Research Council; G0801316//Medical Research Council; G0802158//Medical Research Council; RU54 RR019482/RR/NCRR NIH HHS; //Department of Health; //Wellcome Trust
Reg. No./Substance:
0/CACNA1A protein, human; 0/Calcium Channels; 9007-49-2/DNA

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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