Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel.
A polymorphic CAG repeat was identified in the human alpha 1A voltage-dependent calcium channel subunit. To test the hypothesis that expansion of this CAG repeat could be the cause of an inherited progressive ataxia, we genotyped a large number of unrelated controls and ataxia patients. Eight unrelated patients with late onset ataxia had alleles with larger repeat numbers (21-27) compared to the number of repeats (4-16) in 475 non-ataxia individuals. Analysis of the repeat length in families of the affected individuals revealed that the expansion segregated with the phenotype in every patient. We identified six isoforms of the human alpha 1A calcium channel subunit. The CAG repeat is within the open reading frame and is predicted to encode glutamine in three of the isoforms. We conclude that a small polyglutamine expansion in the human alpha 1A calcium channel is most likely the cause of a newly classified autosomal dominant spinocerebellar ataxia, SCA6.
Zhuchenko
O
O
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Bailey
J
J
Bonnen
P
P
Ashizawa
T
T
Stockton
D W
DW
Amos
C
C
Dobyns
W B
WB
Subramony
S H
SH
Zoghbi
H Y
HY
Lee
C C
CC
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D015220:Calcium Channels / Q000235:genetics*; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000473:pathology; D005260:Female; D005799:Genes, Dominant; D005838:Genotype; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D010455:Peptides / Q000235:genetics*; D011817:Rabbits; D017386:Sequence Homology, Amino Acid; D018911:Trinucleotide Repeats; D020864:Calcium Channels, N-Type
D015220:Calcium Channels; D009419:Nerve Tissue Proteins; D010455:Peptides; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type; C097188:polyglutamine