CACNA1A mutations causing episodic and progressive ataxia alter channel trafficking and kinetics.
ABSTRACT CACNA1A encodes CaV2.1, the pore-forming subunit of P/Q-type voltage-gated calcium channel complexes. Mutations in CACNA1A cause a wide range of neurologic disturbances variably associated with cerebellar degeneration. Functional studies to date focus on electrophysiologic defects that do not adequately explain the phenotypic findings.
To investigate whether some missense mutations might interfere with protein folding and trafficking, eventually leading to protein aggregation and neuronal injury.
The authors studied the functional consequences of two pore missense mutations, C287Y and G293R, in two families with EA2, one newly discovered and the other previously reported. Both mutations caused episodic and interictal ataxia. The biophysical properties of mutant and wild type calcium channels were examined by whole-cell patch-clamp recordings in transfected COS-7 cells. The plasma membrane targeting was visualized by confocal fluorescence imaging on CaV2.1 tagged with green fluorescent protein.
The mutant channels exhibited a marked reduction in current expression and deficiencies in plasma membrane targeting.
In addition to altered channel function, the deficiency in protein misfolding and trafficking associated with the C287Y and G293R mutants may contribute to the slowly progressive cerebellar ataxia.
- Gastroenterology 10/2011; 34(8):585-586. · 12.82 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Spinocerebellar ataxia type 6 (SCA6), episodic ataxia type 2 (EA2) and familial hemiplegic migraine type 1 (FHM1) are allelic disorders of the gene CACNA1A encoding the P/Q subunit of a voltage gated calcium channel. While SCA6 is related to repeat expansions affecting the C-terminal part of the protein, EA2 and FHM phenotypes are usually associated with nonsense and missense mutations leading to impaired channel properties. In three unrelated families with dominant cerebellar ataxia, symptoms cosegregated with CACNA1A missense mutations of evolutionary highly conserved amino acids (exchanges p.E668K, p.R583Q and p.D302N). To evaluate pathogenic effects, in silico, protein modeling analyses were performed which indicate structural alterations of the novel mutation p.E668K within the homologous domain 2 affecting CACNA1A protein function.The phenotype is characterised by a very slowly progressive ataxia, while ataxic episodes or migraine are uncommon. These findings enlarge the phenotypic spectrum of CACNA1A mutations.European journal of medical genetics 01/2014; · 1.57 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Neurological channelopathies are attributed to aberrant ion channelsaffectingCNS, PNS, cardiac and skeletal muscles.To maintain thehomeostasis of excitable tissues; functional ion channels are necessary to rely electrical signalswhereas any malfunctioning serves as an intrinsic factor todevelop neurological channelopathies.Molecular basis of these disease arestudiedbased on genetic and biophysical approaches, e.g. loci positional cloning whereas pathogenesis and bio-behavioralanalysis revealed the dependency ongenetic mutations and inter-current triggering factors.Although, electrophysiological studies revealed the possible mechanisms of diseases but analytical study of ion channels remained unsettled and therefore underlying mechanism in channelopathies is necessary for better clinical application. Herein, we demonstrated (i) structural and functional role of various ion channels(Na+, K+, Ca2+,Cl-), (ii) pathophysiology involved in the onset of their associated channelopathies and (iii) comparative sequence and phylogenetic analysis of diversified sodium, potassium, calcium and chloride ion channel subtypes.Journal of Membrane Biology 07/2014; · 2.48 Impact Factor