Translated Mutation in the Nurr1 Gene as a Cause for Parkinson’s Disease David A. Grimes, MD, 1,2 * Fabin Han, MD, 2 Michel Panisset, MD, 3 Lemuel Racacho, BSc, 2 Fengxia Xiao, PhD, 2 Ruobing Zou, 2 Kelly Westaff, 2 and Dennis E. Bulman, PhD 1,2 1 Department of Medicine, Division of Neurology, Ottawa Hospital, Ottawa, Ontario, Canada 2 Ottawa Health Research Institute, University of Ottawa, Centre for Neuromuscular Disease, Ottawa, Ontario, Canada 3 Department of Neurology, McGill Centre for Studies in Aging, McGill University, Montreal, Quebec, Canada Abstract: Multiple genes have been now identified as causing Parkinson’s disease (PD). In 2003, two mutations were identi- fied in exon 1 of the Nurr1 gene in 10 of 107 individuals with familial PD. To date, investigators have only focused on screening for these known mutations of the Nurr1 gene. All individuals were recruited from two Parkinson’s disease clinics in Canada. Following PCR amplification of each exon of the Nurr1 gene, samples underwent denaturing high-performance liquid chromatography (DHPLC) analysis. Ten individuals also underwent direct sequencing as well as any samples where variants were identified. The Nurr1 gene was evaluated for 202 PD individuals, 37% of whom had at least one relative with PD and 100 control non-PD individuals. Using DHPLC and direct sequencing, we did not detect any sequence variants in exon 1. Variants in amplicon 6 were seen and direct sequencing con- firmed a known NI6P polymorphism in intron 6. Novel poly- morphisms were also identified in exon 3 and intron 5. A novel mutation was identified in exon 3 in one nonfamilial PD indi- vidual. This heterozygous C-to-G transversion resulted in a serine-to-cysteine substitution and was not identified in any of the other 602 chromosomes screened. Mutations in the Nurr1 gene in our large cohort of familial and sporadic PD individuals are rare. The novel mutation in exon 3 is predicted to affect phosphorylation and functional studies to assess this are under- way. This is the first coding mutation identified in the Nurr1 gene for Parkinson’s disease. © 2006 Movement Disorder Society Key words: Nurr1; Parkinson’s disease; NR4AZ; genetics Parkinson’s disease (MIM 168600) is a common pro- gressive neurological disorder where the etiology of the majority of cases is unknown, yet a small but growing subset of individuals has a single gene defect as the cause. The Nurr1 gene (also called NR4A2) is a member of the nuclear receptor superfamily of transcription fac- tors required for the development and survival of mid- brain dopaminergic cells. 1 Increased frequencies of a homozygous or heterozygous polymorphism (NI6P) in intron 6 of Nurr1 have been shown to be associated with familial and sporadic Parkinson’s disease (PD). 2,3 How- ever, this association has not been found by others. 4–8 In 2003, two mutations in the Nurr1 gene were identified in 10 of 107 individuals with familial Parkinson’s disease. 9 One of the mutations, detected in 8 of 107 individuals with familial Parkinson’s disease, was a T deletion at -291, upstream of the initiator AUG codon of Nurr1. The second mutation, detected in 2 of 107 individuals with familial Parkinson’s disease, was a T-to-G substi- tution at nucleotide position -245. These mutations were verified to reduce the level of Nurr1 mRNA, im- plying a dominant negative effect of the mutated allele. 9 These mutations have not been found in other cohorts of PD individuals, 4,5,7,8,10 –12 leading to the speculation by some authors that Nurr1 does not play a role in Parkin- son’s disease at all. 4 Since the originally reported mutations occurred in the 5' untranslated regions of the gene, most investigators have focused on screening only for these mutations in exon 1. Only two studies have screened for novel muta- Drs. Grimes and Han contributed equally to this study. *Correspondence to: Dr. D.A. Grimes, Ottawa Hospital, Civic Cam- pus, 1053 Carling Avenue, Ottawa, K1Y 4E9, Canada. E-mail: dagrimes@ottawahospital.on.ca Received 8 February 2005; Revised 3 May and 13 September 2005; Accepted 19 September 2005 Published online 10 March 2006 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.20820 Movement Disorders Vol. 21, No. 7, 2006, pp. 906 –909 © 2006 Movement Disorder Society 906