POLG1 polyglutamine tract variants associated with Parkinson's disease.
A possible role of allelic variation of the mitochondrial DNA polymerase gamma (POLG1) gene in Parkinson's disease (PD) has been suggested. First, POLG1 missense mutations have been found in patients with familial parkinsonism and mitochondrial myopathy. Second, increased frequency of rare alleles of the POLG1 CAG-repeat (poly-Q) has been found in Finnish idiopathic apparently sporadic PD patients, but conflicting reports exist. The POLG1 poly-Q exhibits one major allele with 10 repeats (10Q, frequency >/=80%) and several less common alleles such as 11Q (frequency 6-9%), 6Q-9Q and 12Q-14Q (frequencies <4%). It is not known, whether the poly-Q variation modulates POLG1 function. Here we sequenced the poly-Q in 641 North American Caucasian PD patients and 292 controls. Caucasian literature controls were also used. Normal allele was defined either as 10/11Q or as 10Q according to the previous literature. The frequency of the non-10/11Q alleles in cases was not significantly different from the controls. Variant alleles defined as non-10Q were significantly increased in the PD patients compared to the North American controls (17.6% vs. 12.3%, p=0.004) as well as compared to the larger set of 897 controls (17.6% vs. 13.2%, p=0.0007). These results suggest that POLG1 poly-Q alleles other than the conserved 10Q allele may increase susceptibility to PD. This finding may be attributable to a beneficial function of the 10Q repeat protein or linkage disequilibrium between the 10Q allele and another variation within or close to POLG1. Other large case-control studies and analyses on functional differences of POLG1 poly-Q variants are warranted.
Eerola
Johanna
J
Department of Neurology, Helsinki University Central Hospital, FIN-00290 Helsinki, Finland.
Luoma
Petri T
PT
Peuralinna
Terhi
T
Scholz
Sonja
S
Paisan-Ruiz
Coro
C
Suomalainen
Anu
A
Singleton
Andrew B
AB
Tienari
Pentti J
PJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005973:Glutamine / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics*; D010455:Peptides / Q000235:genetics*; D018911:Trinucleotide Repeats; D044465:White People
D010455:Peptides; D005973:Glutamine; C097188:polyglutamine; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human
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