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Mutations in NR4A2 associated with familial Parkinson disease

A Corrigendum to this article was published on 01 February 2003


NR4A2, encoding a member of nuclear receptor superfamily1, is essential for the differentiation of the nigral dopaminergic neurons2,3,4. To determine whether NR4A2 is a susceptibility gene for Parkinson disease, we carried out genetic analyses in 201 individuals affected with Parkinson disease and 221 age-matched unaffected controls. We identified two mutations in NR4A2 associated with Parkinson disease (−291Tdel and −245T→G), which map to the first exon of NR4A2 and affect one allele in 10 of 107 individuals with familial Parkinson disease but not in any individuals with sporadic Parkinson disease (n = 94) or in unaffected controls (n = 221). The age at onset of disease and clinical features of these ten individuals were not different from those of individuals with typical Parkinson disease. The mutations resulted in a marked decrease in NR4A2 mRNA levels in transfected cell lines and in lymphocytes of affected individuals. Additionally, mutations in NR4A2 affect transcription of the gene encoding tyrosine hydroxylase. These data suggest that mutations in NR4A2 can cause dopaminergic dysfunction, associated with Parkinson disease.

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Figure 1: Sequence analysis of the first exon of NR4A2.
Figure 2: Pedigrees from available members of ten families with familial Parkinson disease.
Figure 3: Haplotype analysis.
Figure 4: RT–PCR and RT-coupled real-time PCR.

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The authors thank C. Hunter, T. Ashizawa and W. Ondo for referring some of the individuals with Parkinson disease; W. Xie for technical assistance in NR4A2 mutation analysis; O.M. Conneely, T. Ashizawa and Y. Fu for critical review of the manuscript; and Y. Bassiakos for help with statistical analysis. This program was supported by a grant from the US National Institutes of Health, by a research grant from the American Federation for Aging Research to D.K.V. and by the National Parkinson Foundation, Center of Excellence, Baylor College of Medicine.

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Correspondence to Wei-dong Le.

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Le, Wd., Xu, P., Jankovic, J. et al. Mutations in NR4A2 associated with familial Parkinson disease. Nat Genet 33, 85–89 (2003).

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