TY - JOUR
T1 - PARK2 variability in Polish Parkinson's disease patients - interaction with mitochondrial haplogroups
AU - Gaweda-Walerych, Katarzyna
AU - Safranow, Krzysztof
AU - Jasinska-Myga, Barbara
AU - Bialecka, Monika
AU - Klodowska-Duda, Gabriela
AU - Rudzinska, Monika
AU - Czyzewski, Krzysztof
AU - Cobb, Stephanie A.
AU - Slawek, Jaroslaw
AU - Styczynska, Maria
AU - Opala, Grzegorz
AU - Drozdzik, Marek
AU - Nishioka, Kenya
AU - Farrer, Matthew J.
AU - Ross, Owen A.
AU - Wszolek, Zbigniew K.
AU - Barcikowska, Maria
AU - Zekanowski, Cezary
N1 - Funding Information:
Z. K. W and O. A. R are partially supported by the NIH/NINDS 1RC2NS070276 , NS057567 , P50NS072187 , Mayo Clinic Florida (MCF) Research Committee CR programs (MCF #90052018 and MCF #90052030), and the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch (MCF #90052031/PAU #90052).
Funding Information:
K. G-W and M. Bar. were supported by Polish State Committee for Scientific Research grant no. N N401 235134 .
Funding Information:
B. J-M was supported by the Robert and Clarice Smith Fellowship Program and partially by the Pacific Alzheimer Research Foundation (PARF) C06-01 grant. B.J.-M. worked on this project during her clinical research fellowship at the Mayo Clinic Florida.
PY - 2012/6
Y1 - 2012/6
N2 - Aims and objectives: A new pathomechanism of Parkinson's disease (PD) involving regulation of mitochondrial functions was recently proposed. Parkin complexed with mitochondrial transcription factor A (TFAM) binds mtDNA and promotes mitochondrial biogenesis, which is abolished by PARK2 gene mutations. We have previously shown that mitochondrial haplogroups/clusters and TFAM common variation influenced PD risk. We investigate the role of PARK2 polymorphisms on PD risk and their interactions with mitochondrial haplogroups/clusters as well as with TFAM variability. Methods: 104 early-onset PD patients (EOPD, age at onset ≤50 years) were screened for PARK2 coding sequence changes including gene dosage alterations. Three selected PARK2 polymorphisms (S167N, V380L, D394N) were genotyped in 326 PD patients and 315 controls using TaqMan allelic discrimination assay. Results: PARK2 screen revealed two heterozygous changes in two EOPD patients: exon 2 deletion and one novel synonymous variation (c.999C > A, P333P).In association study no differences in genotype/allele frequencies of S167N, V380L, D394N were found between analyzed groups. Stratification by mitochondrial clusters revealed higher frequency of V380L G/G genotype and allele G in PD patients, within HV cluster (p = 0.040; p = 0.022, respectively). Moreover, interaction between genotypes G/G V380L of PARK2 and G/G rs2306604 of TFAM, within HV cluster was significant (OR 2.05; CI 1.04-4.04; p = 0.038). Conclusions: Our results indicate that co-occurrence of G/G V380L PARK2 and G/G rs2306604 TFAM on the prooxidative HV cluster background can contribute to PD risk. We confirm low PARK2 mutation frequency in Polish EOPD patients.
AB - Aims and objectives: A new pathomechanism of Parkinson's disease (PD) involving regulation of mitochondrial functions was recently proposed. Parkin complexed with mitochondrial transcription factor A (TFAM) binds mtDNA and promotes mitochondrial biogenesis, which is abolished by PARK2 gene mutations. We have previously shown that mitochondrial haplogroups/clusters and TFAM common variation influenced PD risk. We investigate the role of PARK2 polymorphisms on PD risk and their interactions with mitochondrial haplogroups/clusters as well as with TFAM variability. Methods: 104 early-onset PD patients (EOPD, age at onset ≤50 years) were screened for PARK2 coding sequence changes including gene dosage alterations. Three selected PARK2 polymorphisms (S167N, V380L, D394N) were genotyped in 326 PD patients and 315 controls using TaqMan allelic discrimination assay. Results: PARK2 screen revealed two heterozygous changes in two EOPD patients: exon 2 deletion and one novel synonymous variation (c.999C > A, P333P).In association study no differences in genotype/allele frequencies of S167N, V380L, D394N were found between analyzed groups. Stratification by mitochondrial clusters revealed higher frequency of V380L G/G genotype and allele G in PD patients, within HV cluster (p = 0.040; p = 0.022, respectively). Moreover, interaction between genotypes G/G V380L of PARK2 and G/G rs2306604 of TFAM, within HV cluster was significant (OR 2.05; CI 1.04-4.04; p = 0.038). Conclusions: Our results indicate that co-occurrence of G/G V380L PARK2 and G/G rs2306604 TFAM on the prooxidative HV cluster background can contribute to PD risk. We confirm low PARK2 mutation frequency in Polish EOPD patients.
KW - Mitochondrial clusters
KW - Mitochondrial transcription factor A (TFAM)
KW - PARK2
KW - Parkinson's disease risk factors
UR - http://www.scopus.com/inward/record.url?scp=84861198221&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84861198221&partnerID=8YFLogxK
U2 - 10.1016/j.parkreldis.2012.01.021
DO - 10.1016/j.parkreldis.2012.01.021
M3 - Article
C2 - 22361577
AN - SCOPUS:84861198221
SN - 1353-8020
VL - 18
SP - 520
EP - 524
JO - Parkinsonism and Related Disorders
JF - Parkinsonism and Related Disorders
IS - 5
ER -