In addition to EA2, the CACNA1A gene is implicated in at least two other autosomal dominant neurological disorders: familial hemiplegic migraine type 1 (FHM1) and spinocerebellar ataxia type 6 (SCA6).
Additionally, CACNA1A gene mutations are known to be associated with epilepsy and biallelic mutations have been reported with an epileptic encephalopathy associated with progressive neurological decline, adding further to the complexity of this gene and the wide phenotypic variability .
The nonsense variant in CACNA1A, whilst previously undescribed, is considered to be pathogenic.
Although it is unclear whether all of these new variants were likely to be pathogenic, these results do highlight the high proportion of patients without a known genetic mutation (52%) and also that variants in genes other than CACNA1A may well contribute to the EA2 phenotype .
It is known that the gene encodes a calcium channel that is predominantly expressed in the cerebellum and this fact may contribute to explain why familial hemiplegic migraine patients with CACNA1A mutations may frequently report central vestibular signs and symptoms.
Tuna et al., "Cerebellar ataxia, hemiplegic migraine, and related phenotypes due to a CACNA1A missense mutation: 12-year follow-up of a large Portuguese family," JAMA Neurology, vol.
Tuna et al., "Phenotypes of spinocerebellar ataxia type 6 and familial hemiplegic migraine caused by a unique CACNA1A missense mutation in patients from a large family," Archives of Neurology, vol.
Shankar et al., "Migrainous vertigo: mutation analysis of the candidate genes CACNA1A, ATP1A2, SCN1A, and CACNB4," Headache, vol.
Multiple mouse strains exist that carry mutations in the orthologous mouse Cacna1a gene, including Rolling Nagoya ([tg.sup.rol]), Tottering (tg) and Leaner ([tg.sup.1a]); these strains arose spontaneously and exhibit phenotypes of cerebellar ataxia often paired with absence epilepsy and/or other motor phenotypes such as dyskinesia and dystonia [5-7].
We utilized highly selective, well-established [GABA.sub.A] receptor ligands to investigate [GABA.sub.A] receptor pharmacology in forebrain membranes of the Cacna1a mutant [tg.sup.rol] and wt littermate control.
3) Effects of Cacna1a mutations are dependent critically on the specific splice isoform of the [Ca.sub.V]2.1 channel.
Giffin ve ark.'lari (10), ailesinde ailevi hemiplejik migren oykusu olan benin paroksismal tortikollisli iki hastada CACNA1A
mutasyonu saptamislar ve bu hastaligin migren "aura" si esdegeri olan bir kalsiyum kanal boslugu olabilecegini iddia etmislerdir.