Variations of the CAG trinucleotide repeat in DNA polymerase gamma (POLG1) is associated with Parkinson's disease in Sweden

DNA polymerase gamma (POLG1) is coding for the catalytic subunit of the heterotrimeric mitochondrial DNA polymerase and involved in replication and repair of mitochondrial DNA. In addition to its 5′ to 3′ polymerase activity, POLG1 has a 3′ to 5′ exonuclease activity important in the repair process. Mitochondrial dysfunction has been implicated in neurodegenerative disorders like Parkinson's disease (PD). Dopamine neurons, which degenerate in PD, are believed to be particularly susceptible to mitochondrial dysfunction, which makes POLG1 a possible candidate gene for the disease. POLG1 has a polyglutamine tract (poly-Q) in the N-terminal, encoded by a CAG sequence in exon 2. Most commonly the poly-Q tract comprises 10 repeats (10Q, frequency >80%) or moderately common 11Q (frequency 6–12%); however the composition of poly-Q alleles has been reported to vary from 6Q to 14Q. We analyzed this POLG1 trinucleotide repeat in a Swedish PD case–control material and detected variations from 5Q to 15Q. We report a significant association between the non-10/11Q repeats with PD (p = 0.002). In silico analysis of poly-Q length effect on mRNA folding energy show a decrease in energy for <10/11Q mRNA (4.6%) and an increase for >10/11Q mRNA (4.8%) compared to 10/11Q mRNA. Our results strengthen the evidence for involvement of POLG1 and mitochondrial dysfunction in PD.

Research highlights▶ We analyzed a POLG1 CAG repeat (poly-Q) in a Swedish PD case–control material. ▶ We detected POLG1 trinucleotide variations from 5Q to 15Q. ▶ We report a significant association with the non-10/11Q repeats and PD (p = 0.002). ▶ We show an effect of poly-Q length on mRNA folding energy in silico.