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NR2A and NR2B receptor gene variations modify age at onset in Huntington disease

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Abstract.

N -Methyl- d -aspartate (NMDA) receptor-mediated excitotoxicity has been proposed to play a role in the pathogenesis of Huntington disease (HD), an autosomal dominantly inherited disorder associated with defined expansions in a stretch of perfect CAG repeats in the 5′ part of the IT15 gene. The number of CAG repeat units is highly predictive for the age at onset (AO) in HD. However, AO is only modestly correlated with repeat length when the HD expansion range is in the high 30s or low 40s. Therefore, we investigated whether the genes for the different subunits composing the multimeric complexes of NMDA receptors (GRIN glutamate receptor, ionotropic, N -methyl- d -aspartate) represent candidates for modulating the AO of HD. In the studied cohort of 167 HD patients, the repeat range from 41 to 45 CAG units accounted for 30.8% of the variance in AO; 12.3% additional variance could be attributed to GRIN2B genotype variation and 4.5% to GRIN2A genotype variation. We conclude that these two genes, coding for NR2B and NR2A subtypes mainly expressed in the striatum, may influence the variability in AO of HD. Neuroprotective strategies for HD patients and persons at risk should be reconsidered in the light of these findings.

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References

  1. Kehoe P, Krawczak M, Harper PS, Owen MJ, Jones AL (1999) Age of onset in Huntington disease: sex specific influence of apolipoprotein E genotype and normal CAG repeat length. J Med Genet 36:108–111

    CAS  PubMed  Google Scholar 

  2. Schwarcz R, Bennett JP Jr, Coyle JT Jr (1977) Loss of striatal serotonin synaptic receptor binding induced by kainic acid lesions: correlations with Huntington’s disease. J Neurochem 4:867–869

    Google Scholar 

  3. Kuppenbender KD, Standaert DG, Feuerstein TJ, Penney JB Jr, Young AB, Landwehrmeyer GB (2000) Expression of NMDA receptor subunit mRNAs in neurochemically identified projection and interneurons in the human striatum. J Comp Neurol 419:407–421

    Article  CAS  PubMed  Google Scholar 

  4. Sheng M, Pak DT (2000) Ligand-gated ion channel interactions with cytoskeletal and signaling proteins. Annu Rev Physiol 62:755–778

    Article  CAS  PubMed  Google Scholar 

  5. Ellison DW, Beal MF, Mazurek MF, Malloy JR, Bird ED, Martin JB (1987) Amino acid neurotransmitter abnormalities in Huntington’s disease and the quinolinic acid animal model of Huntington’s disease. Brain 110:1657–1673

    PubMed  Google Scholar 

  6. Young AB, Greenamyre JT, Hollingsworth Z, Albin R, D’Amato C, Shoulson I, Penney JB (1988) NMDA receptor losses in putamen from patients with Huntington’s disease. Science 241:981–983

    CAS  PubMed  Google Scholar 

  7. Chen N, Luo T, Wellington C, Metzler M, McCutcheon K, Hayden MR, Raymond LA (1999) Subtype-specific enhancement of NMDA receptor currents by mutant huntingtin. J Neurochem 5:1890–1898

    Article  Google Scholar 

  8. Zeron MM, Hansson O, Chen N, Wellington CL, Leavitt BR, Brundin P, Hayden MR, Raymond LA (2002) Increased sensitivity to N -methyl- d -aspartate receptor-mediated excitotoxicity in a mouse model of Huntington’s disease. Neuron 6:849–860

    Article  Google Scholar 

  9. Song C, Zhang Y, Pasons CG, Liu YF (2003) Expression of polyglutamine-expanded huntingtin induces tyrosine phosphorylation of N -methyl- d -aspartate receptors. J Biol Chem 278:33364–33369

    Article  CAS  PubMed  Google Scholar 

  10. Sun Y, Savanenin A, Reddy PH, Liu YF (2001) Polyglutamine-expanded huntingtin promotes sensitization of N -methyl- d -aspartate receptors via post-synaptic density 95. J Biol Chem 276:24713–24718

    Article  CAS  PubMed  Google Scholar 

  11. Warner JP, Barron LH, Brock DJ (1993) A new polymerase chain reaction (PCR) assay for the trinucleotide repeat that is unstable and expanded on Huntington’s disease chromosomes. Mol Cell Probes 7:235–239

    Article  CAS  PubMed  Google Scholar 

  12. Jagiello P, Gencik M, Arning L, Wieczorek S, Kunstmann E, Csernok E, Gross WL, Epplen JT (2004) New genomic region for Wegener’s granulomatosis as revealed by an extended association screen with 202 apoptosis-related genes. Hum Genet 5:468–477

    Article  Google Scholar 

  13. Arning L, Jagiello P, Wieczorek S, Saft C, Andrich J, Epplen JT (2004) Glutathione S-transferase omega 1 variation does not influence age at onset of Huntington’s disease. BMC Med Genet 1:7

    Article  Google Scholar 

  14. Rubinsztein DC, Leggo J, Chiano M (1997) Genotypes at the GluR6 kainate receptor locus are associated with variation in the age of onset of Huntington disease. Proc Natl Acad Sci U S A 94:3872–3876

    Article  CAS  PubMed  Google Scholar 

  15. MacDonald ME, Vonsattel JP, Shrinidhi J, Couropmitree NN, Cupples LA, Bird ED, Gusella JF, Myers RH (1999) Evidence for the GluR6 gene associated with younger onset age of Huntington’s disease. Neurology 6:1330–1332

    Google Scholar 

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Acknowledgements.

We would like to thank Ingrid Alheite for technical support. The experiments comply with current laws in Germany.

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Authors and Affiliations

  1. Department of Human Genetics, Ruhr University Bochum, Universitätsstrasse 150, 44801 Bochum, Germany

    Larissa Arning, Sandra Valentin & Jörg T. Epplen

  2. Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Gudrunstrassse 56, 44791 Bochum, Germany

    Peter H. Kraus, Carsten Saft & Jürgen Andrich

Authors
  1. Larissa Arning
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  2. Peter H. Kraus
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  3. Sandra Valentin
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  4. Carsten Saft
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  5. Jürgen Andrich
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  6. Jörg T. Epplen
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Correspondence to Larissa Arning.

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Arning, L., Kraus, P.H., Valentin, S. et al. NR2A and NR2B receptor gene variations modify age at onset in Huntington disease. Neurogenetics 6, 25–28 (2005). https://doi.org/10.1007/s10048-004-0198-8

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  • DOI: https://doi.org/10.1007/s10048-004-0198-8

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