Progressive ataxia due to a missense mutation in a calcium-channel gene

Am J Hum Genet. 1997 Nov;61(5):1078-87. doi: 10.1086/301613.


We describe a family with severe progressive cerebellar ataxia involving the trunk, the extremities, and speech. The proband, who has prominent atrophy of the cerebellum, shown by magnetic resonance imaging, was confined to a wheelchair at the age of 44 years. Two sons have episodes of vertigo and ataxia that are not responsive to acetazolamide. Quantitative eye-movement testing showed a consistent pattern of abnormalities localizing to the cerebellum. Genotyping suggested linkage to chromosome 19p, and SSCP showed an aberrant migrating fragment in exon 6 of the calcium-channel gene CACNA1A, which cosegregated with the disease. Sequencing of exon 6 identified a G-->A transposition in one allele, at nucleotide 1152, resulting in a predicted glycine-to-arginine substitution at codon 293. The CAG-repeat expansion associated with spinocerebellar ataxia 6 was not present in any family members. This family is unique in having a non-CAG-repeat mutation that leads to severe progressive ataxia. Since a great deal is known about the function of calcium channels, we speculate on how this missense mutation leads to the combination of clinical symptoms and signs.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Calcium Channels / chemistry
  • Calcium Channels / genetics*
  • Cerebellar Ataxia / genetics*
  • Cerebellar Ataxia / pathology
  • Cerebellum / pathology
  • Chromosomes, Human, Pair 19 / genetics
  • Eye Movements
  • Female
  • Genetic Linkage / genetics
  • Haplotypes / genetics
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Microsatellite Repeats
  • Molecular Sequence Data
  • Mutation*
  • Pedigree
  • Phenotype
  • Point Mutation / genetics
  • Polymorphism, Single-Stranded Conformational
  • Sequence Analysis, DNA
  • Trinucleotide Repeats


  • CACNA1A protein, human
  • Calcium Channels

Associated data

  • GENBANK/X99897
  • GENBANK/Z80119