Progressive ataxia due to a missense mutation in a calcium-channel gene.
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.
Yue
Q
Q
Department of Neurology, UCLA School of Medicine, Los Angeles, CA 90095-1769, USA.
Jen
J C
JC
Nelson
S F
SF
Baloh
R W
RW
D000595:Amino Acid Sequence; D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics*; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000473:pathology; D002531:Cerebellum / Q000473:pathology; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D005133:Eye Movements; D005260:Female; D008040:Genetic Linkage / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics; D018807:Polymorphism, Single-Stranded Conformational; D017422:Sequence Analysis, DNA; D018911:Trinucleotide Repeats; D020864:Calcium Channels, N-Type
D015220:Calcium Channels; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type