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Tryptophan hydroxylase-2 gene polymorphisms in rhesus monkeys: association with hypothalamic–pituitary–adrenal axis function and in vitro gene expression

Molecular Psychiatry volume 11, pages 914–928 (2006)Cite this article

Abstract

Tryptophan hydroxylase-2 (TPH2) is a newly identified second form of TPH responsible for serotonin synthesis in the brain and has been increasingly implicated as a contributor to the etiology of various psychiatric disorders. In this study, we have identified the constellation of polymorphisms in rhesus monkey TPH2 and investigated genotype/phenotype association as well as gene expression effects of specific polymorphisms. Genomic DNA was obtained from 247 rhesus monkeys, among which 24 had been previously examined for plasma cortisol level, dexamethasone suppression, and combined dexmethasone/ACTH challenge. Polymorphisms in all exons, splicing junctions and approximately 2 kb of the 5′-flanking region (5′-FR) of TPH2 were identified by sequencing. We identified 17 single nucleotide polymorphisms (SNPs) including two that are predictive of amino-acid change (25Pro>His and 75Gly>Ser, respectively), two mononucleotide repeats, one dinucleotide repeat, and one 159-bp insertion polymorphism. The 3′-UTR polymorphisms were significantly associated with hypothalamic–pituitary–adrenal (HPA) axis activity, especially 2051A>C, which was strikingly correlated with plasma cortisol level in the morning only (F=10.203, P=0.001). Luciferase reporter gene assays showed that the 3′-UTR polymorphisms and haplotypes had a profound effect on in vitro gene expression. Accordingly, these investigations revealed that polymorphisms in 3′-UTR of rhesus monkey TPH2 modulate HPA axis function, presumably by affecting levels of TPH2 expression.

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References

  1. Martinez A, Knappskog PM, Haavik J . A structural approach into human tryptophan hydroxylase and its implications for the regulation of serotonin biosynthesis. Curr Med Chem 2001; 8: 1077–1091.

    Article  CAS  Google Scholar 

  2. Walther DJ, Bader M . A unique central tryptophan hydroxylase isoform. Biochem Pharmacol 2003; 66: 1673–1680.

    Article  CAS  Google Scholar 

  3. Walther DJ, Peter JU, Bashammakh S, Hortnagl H, Voits M, Fink H et al. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 2003; 299: 76.

    Article  CAS  Google Scholar 

  4. Zill P, Buttner A, Eisenmenger W, Bondy B, Ackenheil M . Regional mRNA expression of a second tryptophan hydroxylase isoform in postmortem tissue samples of two human brains. Eur Neuropsychopharmacol 2004; 14: 282–284.

    Article  CAS  Google Scholar 

  5. Malek ZS, Dardente H, Pevet P, Raison S . Tissue-specific expression of tryptophan hydroxylase mRNAs in the rat midbrain: anatomical evidence and daily profiles. Eur J Neurosci 2005; 22: 895–901.

    Article  Google Scholar 

  6. Zhang X, Beaulieu JM, Sotnikova TD, Gainetdinov RR, Caron MG . Tryptophan hydroxylase-2 controls brain serotonin synthesis. Science 2004; 305: 217.

    Article  CAS  Google Scholar 

  7. Zill P, Baghai TC, Zwanzger P, Schule C, Eser D, Rupprecht R et al. SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression. Mol Psychiatry 2004; 9: 1030–1036.

    Article  CAS  Google Scholar 

  8. Zhang X, Gainetdinov RR, Beaulieu JM, Sotnikova TD, Burch LH, Williams RB et al. Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 2005; 45: 11–16.

    Article  CAS  Google Scholar 

  9. Zhou Z, Roy A, Lipsky R, Kuchipudi K, Zhu G, Taubman J et al. Haplotype-based linkage of tryptophan hydroxylase 2 to suicide attempt, major depression, and cerebrospinal fluid 5-hydroxyindoleacetic acid in 4 populations. Arch Gen Psychiatry 2005; 62: 1109–1118.

    Article  CAS  Google Scholar 

  10. Harvey M, Shink E, Tremblay M, Gagne B, Raymond C, Labbe M et al. Support for the involvement of TPH2 gene in affective disorders. Mol Psychiatry 2004; 9: 980–981.

    Article  CAS  Google Scholar 

  11. Zill P, Buttner A, Eisenmenger W, Moller HJ, Bondy B, Ackenheil M . Single nucleotide polymorphism and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene in suicide victims. Biol Psychiatry 2004; 56: 581–586.

    Article  CAS  Google Scholar 

  12. Coon H, Dunn D, Lainhart J, Miller J, Hamil C, Battaglia A et al. Possible association between autism and variants in the brain-expressed tryptophan hydroxylase gene (TPH2). Am J Med Genet B Neuropsychiatr Genet 2005; 135: 42–46.

    Article  Google Scholar 

  13. Mossner R, Walitza S, Geller F, Scherag A, Gutknecht L, Jacob C et al. Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in children and adolescents with obsessive-compulsive disorder. Int J Neuropsychopharmacol 2005; 1–6 [E-pub ahead of print].

  14. Sheehan K, Lowe N, Kirley A, Mullins C, Fitzgerald M, Gill M et al. Tryptophan hydroxylase 2 (TPH2) gene variants associated with ADHD. Mol Psychiatry 2005; 10: 944–949.

    Article  CAS  Google Scholar 

  15. Walitza S, Renner TJ, Dempfle A, Konrad K, Wewetzer Ch, Halbach A et al. Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder. Mol Psychiatry 2005; 10: 1126–1132.

    Article  CAS  Google Scholar 

  16. Blakely RD . Overview: a rare opportunity or just one less reason to be depressed. Neuron 2005; 48: 701–702.

    Article  CAS  Google Scholar 

  17. Zhou Z, Peters EJ, Hamilton SP, McMahon F, Thomas C, McGrath PJ et al. Response to Zhang et al. (2005): loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 45, 11–16. Neuron 2005; 48: 702–703.

    Article  CAS  Google Scholar 

  18. Van Den Bogaert A, De Zutter S, Heyrman L, Mendlewicz J, Adolfsson R, Van Broeckhoven C et al. Response to Zhang et al. (2005): loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 45, 11–16. Neuron 2005; 48: 704.

    Article  CAS  Google Scholar 

  19. Glatt CE, Carlson E, Taylor TR, Risch N, Reus VI, Schaefer CA . Response to Zhang et al. (2005): loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 45, 11–16. Neuron 2005; 48: 704–705.

    Article  CAS  Google Scholar 

  20. Brown SM, Peet E, Manuck SB, Williamson DE, Dahl RE, Ferrell RE et al. A regulatory variant of the human tryptophan hydroxylase-2 gene biases amygdala reactivity. Mol Psychiatry 2005; 10: 884–888, 805.

    Article  CAS  Google Scholar 

  21. Canli T, Congdon E, Gutknecht L, Constable RT, Lesch KP . Amygdala responsiveness is modulated by tryptophan hydroxylase-2 gene variation. J Neural Transm 2005; 112: 1479–1485.

    Article  CAS  Google Scholar 

  22. Tiefenbacher S, Novak MA, Jorgensen MJ, Meyer JS . Physiological correlates of self-injurious behavior in captive, socially-reared rhesus monkeys. Psychoneuroendocrinology 2000; 25: 799–817.

    Article  CAS  Google Scholar 

  23. Tiefenbacher S, Novak MA, Marinos LM, Chase WK, Miller JA, Meyer JS . Altered hypothalamic-pituitary-adrenocortical function in rhesus monkeys (Macaca mulatta) with self-injurous behaviour. Psychoneuroendocrinology 2004; 29: 501–515.

    Article  CAS  Google Scholar 

  24. Zuker M . Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res 2003; 31: 3406–3415.

    Article  CAS  Google Scholar 

  25. Kuersten S, Goodwin EB . The power of the 3′ UTR: translational control and development. Nat Rev Gene 2003; 4: 626–637.

    Article  CAS  Google Scholar 

  26. de Moor CH, Meijer H, Lissenden S . Mechanisms of translational control by the 3′ UTR in development and differentiation. Semin Cell Dev Biol 2005; 16: 49–58.

    Article  CAS  Google Scholar 

  27. Dinan TG . Serotonin and the regulation of hypothalamic-pituitary-adrenal axis function. Life Sci 1996; 58: 1683–1694.

    Article  CAS  Google Scholar 

  28. Lowry CA . Functional subsets of serotonergic neurones: implications for control of the hypothalamic-pituitary-adrenal axis. J Neuroendocrinol 2002; 14: 911–923.

    Article  CAS  Google Scholar 

  29. Clark JA, Pai LY, Flick RB, Rohrer SP . Differential hormonal regulation of tryptophan hydroxylase-2 mRNA in the murine dorsal raphe nucleus. Biol Psychiatry 2005; 57: 943–946.

    Article  CAS  Google Scholar 

  30. Gold PW, Chrousos GP . Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Mol Psychiatry 2002; 7: 254–275.

    Article  CAS  Google Scholar 

  31. Joels M, Verkuyl JM, Van Riel E . Hippocampal and hypothalamic function after chronic stress. Ann NY Acad Sci 2003; 1007: 367–378.

    Article  CAS  Google Scholar 

  32. Bach-Mizrachi H, Underwood MD, Kassir SA, Bakalian MJ, Sibille E, Tamir H et al. Neuronal tryptophan hydroxylase mRNA expression in the human dorsal and median raphe nuclei: major depression and suicide. Neuropsychopharmacology 2006; 31: 814–824.

    Article  CAS  Google Scholar 

  33. Gianoulakis C . Alcohol-seeking behavior: the roles of the hypothalamic-pituitary-adrenal axis and the endogenous opioid system. Alcohol Health Res World 1998; 22: 202–210.

    CAS  PubMed  Google Scholar 

  34. Wand GS, Dobs AS . Alterations in the hypothalamic-pituitary-adrenal axis in actively drinking alcoholics. J Clin Endocrinol Metab 1991; 72: 1290–1295.

    Article  CAS  Google Scholar 

  35. Thayer JF, Hall M, Sollers III JJ, Fischer JE . Alcohol use, urinary cortisol, and heart rate variability in apparently healthy men: evidence for impaired inhibitory control of the HPA axis in heavy drinkers. Int J Psychophysiol 2006; 59: 244–250.

    Article  Google Scholar 

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Acknowledgements

This study was supported by a laboratory start-up package to GMM, DA016606 (GMM) and RR00168. We are grateful to the NEPRC sequencing core for their great help with DNA sequencing. We also thank Dina Yang, Bin Jia, Mary Bahn, and Bertha Madras for their support for this study.

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Authors and Affiliations

  1. Division of Neurochemistry, Harvard Medical School, New England Primate Research Center, Southborough, MA, USA

    G-L Chen, S Hakim, Z Xie & G M Miller

  2. Department of Psychology, University of Massachusetts at Amherst, Amherst, MA, USA

    M A Novak

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  1. G-L Chen
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Correspondence to G M Miller.

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Chen, GL., Novak, M., Hakim, S. et al. Tryptophan hydroxylase-2 gene polymorphisms in rhesus monkeys: association with hypothalamic–pituitary–adrenal axis function and in vitro gene expression. Mol Psychiatry 11, 914–928 (2006). https://doi.org/10.1038/sj.mp.4001870

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