title: POLG1 polyglutamine tract variants associated with Parkinson's disease.
abstract: 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.
authors.affiliation: Department of Neurology, Helsinki University Central Hospital, FIN-00290 Helsinki, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Eerola
authors.forename: Petri T
authors.initials: PT
authors.lastname: Luoma
authors.forename: Terhi
authors.initials: T
authors.lastname: Peuralinna
authors.forename: Sonja
authors.initials: S
authors.lastname: Scholz
authors.forename: Coro
authors.initials: C
authors.lastname: Paisan-Ruiz
authors.forename: Anu
authors.initials: A
authors.lastname: Suomalainen
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Singleton
authors.forename: Pentti J
authors.initials: PJ
authors.lastname: Tienari
mesh_terms: 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
chemical_list: D010455:Peptides; D005973:Glutamine; C097188:polyglutamine; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human
references.citation: Lancet Neurol. 2008 Jan;7(1):97-109
references.pmid: 18093566
references.citation: Lancet. 2004 Sep 4-10;364(9437):875-82
references.pmid: 15351195
references.citation: Neurosci Lett. 2005 Mar 7;376(1):56-9
references.pmid: 15694274
references.citation: Brain. 2009 Jul;132(Pt 7):1783-94
references.pmid: 19286695
references.citation: Lancet. 1989 Jun 3;1(8649):1269
references.pmid: 2566813
references.citation: Neurology. 2007 Sep 11;69(11):1152-9
references.pmid: 17846414
references.citation: Hum Mol Genet. 2006 Oct 15;15 Spec No 2:R244-52
references.pmid: 16987890
references.citation: J Clin Endocrinol Metab. 2004 Sep;89(9):4292-7
references.pmid: 15356024
references.citation: Trends Neurosci. 2008 Oct;31(10):521-8
references.pmid: 18778858
references.citation: N Engl J Med. 2006 Jan 26;354(4):424-5
references.pmid: 16436782
references.citation: Mov Disord. 2009 May 15;24(7):1092-4
references.pmid: 19243043
references.citation: Mov Disord. 2008 May 15;23(7):1024-1031
references.pmid: 18398914
references.citation: Nat Genet. 2006 May;38(5):515-7
references.pmid: 16604074
references.citation: Hum Biol. 2005 Jun;77(3):355-65
references.pmid: 16392637
references.citation: Ann Neurol. 2006 May;59(5):859-62
references.pmid: 16634032
references.citation: N Engl J Med. 2000 Dec 14;343(24):1765-70
references.pmid: 11114315
references.citation: Mamm Genome. 2004 Jun;15(6):492-502
references.pmid: 15181541
references.citation: Nat Genet. 2001 Nov;29(3):261-2
references.pmid: 11687794
references.citation: Parkinsonism Relat Disord. 2008 Dec;14(8):652-4
references.pmid: 18321754
references.citation: N Engl J Med. 2006 Jan 26;354(4):422-3
references.pmid: 16436781
references.citation: Mol Genet Metab. 2004 Jan;81(1):70-3
references.pmid: 14728994
references.citation: Ann Neurol. 2005 Apr;57(4):535-41
references.pmid: 15786467
references.citation: Nat Genet. 2006 May;38(5):518-20
references.pmid: 16604072
references.citation: Hum Mol Genet. 2001 Aug 15;10(17):1847-51
references.pmid: 11532993
references.citation: Ann Neurol. 1999 May;45(5):577-82
references.pmid: 10319879
references.citation: JAMA. 1999 Jan 27;281(4):341-6
references.pmid: 9929087
references.citation: Neurology. 2006 Nov 14;67(9):1698-700
references.pmid: 16943369
references.citation: Ann Neurol. 1995 Jun;37(6):714-22
references.pmid: 7778844
references.citation: Neurology. 2008 Jul 1;71(1):28-34
references.pmid: 18509094
references.citation: Arch Neurol. 2007 Apr;64(4):553-7
references.pmid: 17420318
references.citation: Science. 1983 Feb 25;219(4587):979-80
references.pmid: 6823561
references.citation: Brain Res. 1984 Feb 6;292(2):390-4
references.pmid: 6607092
references.citation: Neuron. 2002 Aug 29;35(5):819-22
references.pmid: 12372277
references.citation: Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3320-3
references.pmid: 9096391
references.citation: Lancet. 2009 Jun 13;373(9680):2055-66
references.pmid: 19524782
references.citation: Ann Oncol. 2008 Nov;19(11):1910-4
references.pmid: 18632724