PARK2 variability in Polish Parkinson¡¯s disease patients - interaction with mitochondrial haplogroups

详细信息    查看全文

• 作者：Katarzyna Gaweda-Walerych^a ; ^{kasiawal@libero.it} ; Krzysztof Safranow^b ; Barbara Jasinska-Myga^c ; Monika Bialecka^d ; Gabriela Klodowska-Duda^c ; Monika Rudzinska^e ; Krzysztof Czyzewski^f ; Stephanie A. Cobb^g ; Jaroslaw Slawek^h ; ⁱ ; Maria Styczynska^a ; Grzegorz Opala^c ; Marek Drozdzik^d ; Kenya Nishioka^g ; Matthew J. Farrer^g ; Owen A. Ross^g ; Zbigniew K. Wszolek^j ; Maria Barcikowska^a ; Cezary Zekanowski^a
• 关键词：Parkinson&rsquo ; s disease risk factors ; PARK2 ; Mitochondrial clusters ; Mitochondrial transcription factor A (TFAM)
• 刊名：Parkinsonism and Related Disorders
• 出版年：2012
• 出版时间：June, 2012
• 年：2012
• 卷：18
• 期：5
• 页码：520-524
• 全文大小：145 K

文摘

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 ?0 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.