Association of homozygous 7048G7049 variant in the intron six of Nurr1 gene with Parkinson's disease

Objective: To determine whether the Nurr1 gene, which is critical for the development and maintenance of nigral dopaminergic neurons, is a risk factor associated with PD. Background: The Nurrl gene is highly expressed in the dopaminergic neurons in the midbrain. Knockout of the gene results in agenesis of nigral dopaminergic neurons and heterozygous knockout mice increases 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. Methods: This study included 105 patients with familial PD (fPD) and 120 patients with sporadic PD (sPD) and 221 age-matched healthy control subjects. The polymorphisms and mutations of the Nurr1 gene in patients with PD were initially examined by heteroduplex analysis and sequencing analysis from PCR-amplified Nurr1 gene fragments. A polymorphism in the BseRI restriction site was identified, and a relatively large-scale analysis then was conducted by three independent investigators who were blinded to the clinical status of the subjects. Results: A homozygous 7048G7049 polymorphism was found in intron 6 of the Nurr1 gene, which was significantly higher in fPD (10/105; 9.5%) and in sPD (5/120; 4.2%) compared with healthy control subjects (2/221; 0.9%). The mean age and the SD at onset of these homozygote patients with PD was 52 +/- 15 years for fPD and 46 7 years for sPD. The clinical features of these homozygote patients with PD did not differ from those of typical PD. Conclusions: The homozygote polymorphism of 7048G7049 in intron 6 of the Nurr1 gene is associated with typical PD.