Knockdown of Cav2.1 calcium channels is sufficient to induce neurological disorders observed in natural occurring Cacna1a mutants in mice.
The CACNA1A gene encodes the poreforming, voltage-sensitive subunit of the voltage-dependent Ca(v)2.1 calcium channel. Mutations in this gene have been linked to several human disorders, including familial hemiplegic migraine type 1, episodic ataxia type 2, and spinocerebellar ataxia type 6. In mice, mutations of the homolog Cacna1a cause recessively inherited phenotypes in tottering, rolling Nagoya, rocker, and leaner mice. Here we describe two knockdown mice with 28.4+/-3.4% and 13.8+/-3.3% of the wild-type Ca(v)2.1 quantity. 28.4+/-3.4% level mutants displayed ataxia, absence-like seizures and progressive cerebellar atrophy, although they had a normal life span. Mutants with 13.8+/-3.3% level exhibited ataxia severer than the 28.4+/-3.4% level mutants, absence-like seizures and additionally paroxysmal dyskinesia, and died premature around 3 weeks of age. These results indicate that knock down of Ca(v)2.1 quantity to 13.8+/-3.3% of the wild-type level are sufficient to induce the all neurological disorders observed in natural occurring Cacna1a mutants. These knockdown animals with Ca(v)2.1 calcium channels intact can contribute to functional studies of the molecule in the disease.
Saito
Hiromitsu
H
Department of Animal Genomics, Functional Genomics Institute, Mie University Life Science Research Center, Tsu, Mie, Japan.
Okada
Motohiro
M
Miki
Takafumi
T
Wakamori
Minoru
M
Futatsugi
Akira
A
Mori
Yasuo
Y
Mikoshiba
Katsuhiko
K
Suzuki
Noboru
N
D000818:Animals; D020864:Calcium Channels, N-Type / Q000235:genetics*; D020865:Calcium Channels, P-Type / Q000235:genetics*; D020907:Calcium Channels, Q-Type / Q000235:genetics*; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D055724:Electrophysiological Phenomena; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains
D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type