Complete loss of P/Q calcium channel activity caused by a CACNA1A missense mutation carried by patients with episodic ataxia type 2

被引:114
作者
Guida, S
Trettel, F
Pagnutti, S
Mantuano, E
Tottene, A
Veneziano, L
Fellin, T
Spadaro, M
Stauderman, KA
Williams, ME
Volsen, S
Ophoff, RA
Frants, RR
Jodice, C
Frontali, M
Pietrobon, D
机构
[1] Univ Roma Tor Vergata, Dept Biol, Rome, Italy
[2] CNR, Inst Expt Med, Rome, Italy
[3] Univ La Sapienza, Ist Clin Malattie Nervose & Mentali, Rome, Italy
[4] Univ Padua, Ctr Biomembranes, Natl Res Council, Padua, Italy
[5] Univ Padua, Dept Biomed Sci, Padua, Italy
[6] SIBIA Neurosci, La Jolla, CA USA
[7] Eli Lilly Co Ltd, Lilly Res Ctr, Windlesham, Surrey, England
[8] Univ Calif Los Angeles, Ctr Neurobehav Genet, Dept Psychiat & Human Genet, Los Angeles, CA USA
[9] Leiden Univ, Med Ctr, Dept Human & Clin Genet, Ctr Med Genet, Leiden, Netherlands
关键词
D O I
10.1086/318804
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Familial hemiplegic migraine, episodic ataxia type 2 (EA2), and spinocerebellar ataxia type 6 are allelic disorders of the CACNA1A gene (coding for the alpha (1A) subunit of P/Q calcium channels), usually associated with different types of mutations (missense, protein truncating, and expansion, respectively). However, the finding of expansion and missense mutations in patients with EA2 has blurred this genotype-phenotype correlation. We report the first functional analysis of a new missense mutation, associated with an EA2 phenotype-that is, T-->C transition of nt 4747 in exon 28, predicted to change a highly conserved phenylalanine residue to a serine at codon 1491, located in the putative transmembrane segment S6 of domain III. Patch-clamp recording in HEK 293 cells, coexpressing the mutagenized human alpha (1A-2) subunit, together with human beta (4) and alpha (2)delta subunits, showed that channel activity was completely abolished, although the mutated protein is expressed in the cell. These results indicate that a complete loss of P/Q channel function is the mechanism underlying EA2, whether due to truncating or to missense mutations.
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收藏
页码:759 / 764
页数:6
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