Association of moderate polyglutamine tract expansions in the slow calcium-activated potassium channel type 3 with ataxia.
BACKGROUND
The small-conductance calcium-activated potassium channel gene (hSKCa3) contains 2 CAG repeats, 1 of which is highly polymorphic. Although this repeat is not pathologically expanded in patients with schizophrenia, some studies have suggested an allelic association with schizophrenia. CAG expansions in other genes such as the alpha1 subunit of a brain-specific P/Q-type calcium channel gene cause spinocerebellar ataxia type 6, whereas the length of the CAG repeat in the RAI1 gene modifies the age of onset of spinocerebellar ataxia type 2.


OBJECTIVE
To evaluate expansions in the hSKCa3 polyglutamine domain as causative for ataxia, and to study the association between the length of the polyglutamine repeat and the presence of ataxia.


METHODS
We analyzed this repeat in 122 patients with autosomal dominant cerebellar ataxia, or sporadic ataxia, and compared allele distribution with 750 alleles seen in 2 healthy control groups and 172 alleles in patients with Parkinson disease.


RESULTS
The distribution of alleles in ataxia patients and controls was significantly different by Wilcoxon rank test (P <.001). Twenty-two or more polyglutamine tracts were more common in ataxia patients compared with controls by chi2 analysis (P<.001).


CONCLUSIONS
Longer stretches of polyglutamines in a human potassium channel are not causative for ataxia, but they are associated with the presence of ataxia. There is no association with the presence of Parkinson disease.
Figueroa
K P
KP
Division of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. pulst@cshs.org
Chan
P
P
Schöls
L
L
Tanner
C
C
Riess
O
O
Perlman
S L
SL
Geschwind
D H
DH
Pulst
S M
SM
D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001259:Ataxia / Q000235:genetics*; D001483:Base Sequence; D001921:Brain / Q000503:physiopathology*; D005260:Female; D006801:Humans; D008297:Male; D010300:Parkinson Disease / Q000235:genetics; D010455:Peptides / Q000235:genetics*; D011110:Polymorphism, Genetic; D015221:Potassium Channels / Q000235:genetics*; D024681:Potassium Channels, Calcium-Activated; D012016:Reference Values; D012559:Schizophrenia / Q000235:genetics; D051640:Small-Conductance Calcium-Activated Potassium Channels; D020754:Spinocerebellar Ataxias / Q000145:classification / Q000235:genetics*; D018454:Spouses; D018911:Trinucleotide Repeats
C406328:KCNN3 protein, human; D010455:Peptides; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D051640:Small-Conductance Calcium-Activated Potassium Channels; C097188:polyglutamine