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Mutations in NR4A2 associated with familial Parkinson disease

Nature Genetics volume 33, pages 85–89 (2003)Cite this article

A Corrigendum to this article was published on 01 February 2003

Abstract

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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References

  1. Law, S.W., Conneely, O.M., DeMayo, F.J. & O'Malley, B.W. Identification of a new brain-specific transcription factor, Nurr1. Mol. Endocrinol. 6, 2129–2135 (1992).

    CAS  PubMed  Google Scholar 

  2. Zetterström, R.H. et al. Dopamine neuron agenesis in Nurr1-deficient mice. Science 276, 248–250 (1997).

    Article  PubMed  Google Scholar 

  3. Saucedo-Cardenas, O. et al. Nurr1 is essential for the induction of the dopaminergic phenotype and the survival of ventral mesencephalic late dopaminergic precursor neurons. Proc. Natl. Acad. Sci. USA 95, 4013–4018 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Castillo, S.O. et al. Dopamine biosynthesis is selectively abolished in substantia nigra-ventral tegmental area but not in hypothalamic neurons in mice with targeted disruption of the Nurr1 gene. Mol. Cell. Neurosci. 11, 36–46 (1998).

    Article  CAS  PubMed  Google Scholar 

  5. Langston, J.W. Epidemiology versus genetics in Parkinson's disease: progress in resolving an age-old debate. Ann. Neurol. 1 (Suppl), S45–S52 (1998).

    Article  Google Scholar 

  6. Funayama, M. et al. A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2–q13.1. Ann. Neurol. 51, 296–301 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Polymeropoulos, M.H. et al. Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science 276, 2045–2047 (1997).

    CAS  PubMed  Google Scholar 

  8. Kitada, T. et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605–608 (1998).

    Article  CAS  PubMed  Google Scholar 

  9. Martin, E.D. et al. Association of single-nucleotide polymorphisms of the tau gene with late-onset Parkinson disease. JAMA 286, 2239–2324 (2001).

    Article  Google Scholar 

  10. Hicks, A.A. et al. A susceptibility gene for late-onset idiopathic Parkinson's disease. Ann. Neurol. 52, 549–555 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Leroy, E. et al. The ubiquitin pathway in Parkinson's disease. Nature 396, 451–452 (1998).

    Article  Google Scholar 

  12. Valente, E.M. et al. Localization of a novel locus for autosomal recessive early-onset parkinsonism, PARK6, on human chromosome 1p35–p36. Am. J. Hum. Genet. 68, 895–900 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Van Duijn, C.M. et al. PARK7, a novel locus for autosomal recessive early-onset parkinsonism, on chromosome 1p36. Am. J. Hum. Genet. 69, 629–634 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gasser, T. et al. A susceptibility locus for Parkinson's disease maps to chromosome 2p13. Nat. Genet. 18, 262–265 (1998).

    Article  CAS  PubMed  Google Scholar 

  15. Farrer, M.J. et al. A chromosome 4p haplotype segregating with Parkinson's disease and postural tremor. Hum. Mol. Genet. 8, 81–85 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. Saucedo-Cardenas, O. & Conneely, O.M. Comparative distribution of Nurr1 and Nur77 nuclear receptors in the mouse central nervous system. J. Mol. Neurosci. 7, 51–63 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Zetterstrom, R.H., Williams, R., Perlmann, T. & Olson, L. Cellular expression of the immediate early transcription factors Nurr1 and NGFI-B suggests a gene regulatory role in several brain regions including the nigro-striatal dopamine system. Mol. Brain. Res. 41, 111–120 (1996).

    Article  CAS  PubMed  Google Scholar 

  18. Le, W.D. et al. Selective agenesis of mesencephalic dopaminergic neurons in Nurr1 deficient mice. Exp. Neurol. 159, 451–458 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Le, W.D., Conneely, O.M., He, Y., Jankovic, J. & Appel, S.H. Reduced Nurr1 expression increases the vulnerability of mesencephalic dopamine neurons to MPTP-induced injure. J. Neurochem. 73, 2218–2221 (1999).

    CAS  PubMed  Google Scholar 

  20. Mages, H.W., Rilke, O., Bravo, R., Senger, G. & Kroczek, R.A. NOT, a human immediate-early response gene closely related to the steroid/thyroid hormone receptor NAK1/TR3. Mol. Endocrinol. 8, 1583–1591 (1994).

    CAS  PubMed  Google Scholar 

  21. Ichinose, H. et al. Molecular cloning of the human Nurr1 gene: characterization of the human gene and cDNA. Gene 230, 233–239 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Castillo, S.O., Xiao, Q., Lyu, M.S., Kozak, C.A. & Nikodem, V.M. Organization, sequence, chromosomal localization, and promoter identification of the mouse orphan nuclear receptor Nurr1 gene. Genomics 41, 250–257 (1997).

    Article  CAS  PubMed  Google Scholar 

  23. Torii, T., Kawarai, S., Nakamura, H. & Kawakami, H. Organization of the human orphan nuclear receptor Nurr1 gene. Gene 230, 225–232 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. Iwawaki, T., Kohno, K. & Kobayashi, K. Identification of a potential Nurr1 response element that activates the tyrosine hydroxylase gene promoter in cultured cells. Biochem. Biophys. Res. Comm. 274, 590–595 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Sacchetti, P., Mitchell, T.R., Grameman, J.G. & Bannon, M.J. Nurr1 enhances transcription of the human dopamine transporter gene through a novel mechanism. J. Neurochem. 76, 1565–1572 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Buervenich, S. et al. NURR1 mutations in cases of schizophrenia and manic-depressive disorder. Am. J. Med. Gen. 96, 808–813 (2000).

    Article  CAS  Google Scholar 

  27. Chen, Y.H., Tsai, M.T., Shaw, C-K. & Chen, C.H. Mutation analysis of the human NR4A2 gene, an essential gene for midbrain dopaminergic neurogenesis, in Schizophrenic patients. Am. J. Med. Gen. 108, 753–757 (2001).

    Article  Google Scholar 

  28. Nataraj, A.J., Olivos-Glander, I., Kurusawa, N. & Highsmith, W.E. Jr. Single-strand conformation polymorphism and heteroduplex analysis for gel-based mutation detection. Electrophoresis 20, 1177–1185 (1999).

    Article  CAS  PubMed  Google Scholar 

  29. Healy, D.G., Sleiman, P., Sweeney, M.G., Eunson, L.H. & Wood, N.W. Exon 1 gene mutations are rare in familial PD. Mov. Disord. 17 (Suppl), S34 (2002).

  30. Scott, W.K. et al. Complete genomic screen in Parkinson disease: evidence for multiple genes. JAMA 286, 2239–2244 (2001).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

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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Author notes

  1. Demetrios K. Vassilatis

    Present address: Primal, Inc., Seattle, Washington, USA

  2. Wei-dong Le, Pingyi Xu and Joseph Jankovic: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Baylor College of Medicine, One Baylor Plaza, Houston, 77030, Texas, USA

    Wei-dong Le, Pingyi Xu, Joseph Jankovic & Stanley H. Appel

  2. Huffington Center on Aging and Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, 77030, Texas, USA

    Hong Jiang, Roy G. Smith & Demetrios K. Vassilatis

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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). https://doi.org/10.1038/ng1066

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