Mitochondrial DNA polymerase gamma variants in idiopathic sporadic Parkinson disease P.T. Luoma, MSc J. Eerola, MD S. Ahola, BSc A.H. Hakonen, MB O. Hellstro ¨ m, MD K.T. Kivisto ¨ , MD, PhD P.J. Tienari, MD, PhD A. Suomalainen, MD, PhD ABSTRACT Objective: Dysfunction of mitochondrial DNA polymerase gamma (POLG) has been recently recog- nized as an important cause of inherited neurodegenerative diseases. We have reported dominant and recessive inheritance of parkinsonism, mitochondrial myopathy, and premature amenorrhea in five ethnically distinct families with POLG1 mutations. This prompted us to carry out a detailed analysis of the coding region and intron-exon boundaries of POLG1 in Finnish patients with idio- pathic sporadic Parkinson disease (PD) and in nonparkinsonian controls. Methods: The coding region of POLG1 was analyzed in 140 Finnish patients with PD and their 127 spouses as age- and ethnically matched controls. Further, we analyzed the intragenic CAG- repeat region of POLG1 in 126 additional patients with nonparkinsonian neurologic disorders and in 516 Finnish population controls. Results: We found clustering of rare variants of the POLG1 CAG-repeat, encoding a polyglutamine tract, in Finnish patients with idiopathic PD as compared to their spouses (p = 0.003; OR 3.01, 95% CI 1.35 to 6.71), population controls (p = 0.001; OR 2.45, 95% CI 1.45 to 4.14), and patients with nonparkinsonian neurologic disorders (p = 0.05, OR 1.98, 95% CI 0.97 to 4.05). We found several amino acid substitutions, none of them associating with PD. These included a previously parkinsonism-associated POLG variant Y831C, found in one patient with PD, but also in five controls, suggesting that it is a neutral amino acid polymorphism. Conclusions: Our results suggest that POLG polyglutamine tract variants should be considered as a predisposing genetic factor in idiopathic sporadic Parkinson disease. Neurology ® 2007;69:1152–1159 GLOSSARY aa = amino acid; -CIT-SPECT = 123 I--CIT single photon emission tomography; DAT = dopamine transporter; DM = diabe- tes mellitus; FA = atrial fibrillation; IHD = ischemic heart disease; mtDNA = mitochondrial DNA; NA = not analyzed; OND = other neurologic disease group; PD = Parkinson disease; POLG1 = polymerase gamma gene, catalytic subunit; POLG = polymerase gamma protein, catalytic subunit; polyQ = polyglutamine; SpC = spouse controls. Increasing evidence supports an important role for mitochondrial dysfunction in Parkin- son disease (PD). Familial parkinsonism can be caused by mutations in PINK1 (PARK6), DJ-1 (PARK7), or parkin (PARK2), which either localize to mitochondria or are associ- ated with their dysfunction. 1-5 Chemical inhibition of mitochondrial respiratory chain results in dopaminergic neuron loss and parkinsonism. 6-8 Dopaminergic neurons of pa- tients with PD also show increased amounts of mitochondrial DNA (mtDNA) mutations. 9 We reported mutations in the catalytic -subunit of mitochondrial DNA polymerase gamma gene (OMIM no. 174763, POLG1) in families with progressive external ophthal- moplegia, premature menopause, and parkinsonism. 10 Positron emission tomography From Research Program of Molecular Neurology, Biomedicum-Helsinki, Helsinki University, and Department of Neurology, Helsinki University Central Hospital (P.T.L, J.E., S.A., A.H.H., P.J.T., A.S.); Seina ¨joki Central Hospital (O.H.); and Department of Pharmacological Sciences (K.T.K), Tampere University, Finland. Supported by Sigrid Juselius Foundation, Academy of Finland and Helsinki University, Helsinki University Central Hospital, Finnish Cultural Foundation, and the National Graduate School of Clinical Investigation. Disclosure: P.T.L. and A.S. have filed a patent application concerning the results presented in a previous article (Luoma P, Melberg A, Rinne JO, et al. Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study. Lancet 2004;364:875– 882). Address correspondence and reprint requests to Dr. Anu Suomalainen, Biomedicum- Helsinki, Research Program of Molecular Neurology, Room c523B, University of Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland anu.wartiovaara@helsinki.fi 1152 Copyright © 2007 by AAN Enterprises, Inc.