A novel missense mutation in CACNA1A evaluated by in silico protein modeling is associated with non-episodic spinocerebellar ataxia with slow progression

Eur J Med Genet. 2014 Apr;57(5):207-11. doi: 10.1016/j.ejmg.2014.01.005. Epub 2014 Jan 29.


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.

Keywords: CACNA1A; EA2; FHM1; Ion channel gene defects; Molecule dynamic simulation; SCA6; Spinocerebellar ataxia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Calcium Channels / genetics*
  • Cerebellum / abnormalities
  • Cerebellum / pathology
  • DNA Mutational Analysis
  • Disease Progression
  • Female
  • Genetic Association Studies
  • Humans
  • Male
  • Middle Aged
  • Models, Molecular
  • Mutation, Missense*
  • Protein Structure, Tertiary
  • Spinocerebellar Ataxias / genetics*
  • Spinocerebellar Ataxias / pathology


  • CACNA1A protein, human
  • Calcium Channels