Dramatically different levels of cacna1a gene expression between pre-weaning wild type and leaner mice

Abstract

Loss of function mutations of the CACNA1A gene, coding for the α1A subunit of P/Q type voltage-gated calcium channel (Ca V 2.1), are responsible for Episodic Ataxia type 2 (EA2), an autosomal dominant disorder. A dominant negative effect of the EA2 mutated protein, rather than a haploinsufficiency mechanism, has been hypothesised both for protein-truncating and missense mutations. We analysed the cacna1a mRNA expression in leaner mice carrying a cacna1a mutation leading to a premature stop codon. The results showed a very low mutant mRNA expression compared to the wild type allele. Although the mutant mRNA slightly increases with age, its low level is likely due to degradation by nonsense mediated decay, a quality control mechanism that selectively degrades mRNA harbouring premature stop codons. These data have implications for EA2 in humans, suggesting a haploinsufficiency mechanism at least for some of the CACNA1A mutations leading to a premature stop codon.

Mutation Spectrum in the CACNA1A Gene in 49 Patients with Episodic Ataxia

“…Thus, although truncating mutations have usually shown to cause a loss of function of the mutated subunit, the underlying pathophysiological mechanism that causes the EA2 phenotype remains still unclear. Two hypotheses have been proposed: haploinsufficiency, supported by the finding of nonsense mediated RNA decay (NMD) 15, 28 , and a dominant negative effect of the mutated subunit. The latter is more generally accepted as the major mechanism on the basis of functional studies that support an altered interaction between the WT and the mutated allele that would retain the complex in the endoplasmic reticulum, affecting protein trafficking and activating the proteasome response 17, 29, 30 .…”