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Identification and analysis of new sequence variants in the human tryptophan hydroxylase (TpH) gene

Abstract

The tryptophan hydroxylase (TpH) gene codes for the rate-limiting enzyme in serotonin biosynthesis. It is one of the major candidate genes for psychiatric and behavioral disorders. A polymorphism in TpH intron 7 has been shown to be associated with suicidal attempts, aggressive behavior and psychiatric illnesses. By systematically screening the TpH genomic sequence, we identified and confirmed an earlier report of four variants in the promoter region and localized six new sequence variants, ie two in intron 1b, one in exon 1c, one in intron 8, one in intron 9 and a microsatellite in the 3′ region, 5687 bp downstream of the last exon 11. We analyzed these polymorphisms, as well as the one in intron 7, by Single Strand Conformation Analysis, microsatellite or restriction analysis in a collection of 175 West European Caucasian healthy subjects. The four variants in the promoter region are in complete linkage disequilibrium (frequencies of G-T-G-T and T-C-A-G haplotypes are 0.41 and 0.59, respectively). Deletion of GTT in intron 1b is rare (0.7%) and so not informative. The rarer allele T of intron 1b polymorphism T3792A has a frequency of 0.34 and is in partial linkage disequilibrium with the more common alleles of intron 7, 8 and 9. The polymorphisms of these three introns are in complete linkage disequilibrium and the frequencies of haplotypes A-T-C and C-C-T are 0.36 and 0.64 respectively. We detected 10 different alleles in the microsatellite localized in the 3′ region; allele ‘194’ is in partial linkage disequilibrium with haplotype A-T-C of introns 7, 8, and 9. Analysis of these different polymorphisms will constitute an important tool for future studies between the TpH gene and psychiatric disorders.

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References

  1. Jequier E, Robinson DS, Lovenberg W, Sjoerdsma A . Further studies on tryptophan hydroxylase in rat brainstem and beef pineal Biochem Pharmacol 1969; 18: 1071–1081

    Article  CAS  PubMed  Google Scholar 

  2. Grahame-Smith DG . Tryptophan hydroxylation in brain Biochem Biophys Res Commun 1964; 16: 586–592

    Article  CAS  PubMed  Google Scholar 

  3. Boularand S, Darmon MC, Ganem Y, Launay JM, Mallet J . Complete coding sequence of human tryptophan hydroxylase Nucleic Acids Res 1990; 18: 4257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Boularand S, Darmon MC, Ravassard P, Mallet J . Characterization of the human tryptophan hydroxylase gene promoter. Transcriptional regulation by cAMP requires a new motif distinct from the cAMP-responsive element J Biol Chem 1995; 270: 3757–3764

    Article  CAS  PubMed  Google Scholar 

  5. Wang GA, Coon SL, Kaufman S . Alternative splicing at the 3′-cDNA of human tryptophan hydroxylase J Neurochem 1998; 71: 1769–1772

    Article  CAS  PubMed  Google Scholar 

  6. Craig SP, Boularand S, Darmon MC, Mallet J, Craig IW . Localization of human tryptophan hydroxylase (TPH) to chromosome 11p15.3–p14 by in situ hybridization Cytogenet Cell Genet 1991; 56: 157–159

    Article  CAS  PubMed  Google Scholar 

  7. Nielsen DA, Dean M, Goldman D . Genetic mapping of the human tryptophan hydroxylase gene on chromosome 11, using an intronic conformational polymorphism Am J Hum Genet 1992; 51: 1366–1371

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Jacobs BL, Azmitia EC . Structure and function of the brain serotonin system Physiol Rev 1992; 72: 165–229

    Article  CAS  PubMed  Google Scholar 

  9. Roy A, De Jong J, Linnoila M . Cerebrospinal fluid monoamine metabolites and suicidal behavior in depressed patients. A 5-year follow-up study Arch Gen Psychiatry 1989; 46: 609–612

    Article  CAS  PubMed  Google Scholar 

  10. Roy A, Adinoff B, Linnoila M . Acting out hostility in normal volunteers: negative correlation with levels of 5HIAA in cerebrospinal fluid Psychiatry Res 1988; 24: 187–194

    Article  CAS  PubMed  Google Scholar 

  11. Van Praag H, de Hann S . Depression vulnerability and 5-hydroxytryptophan prophylaxis Psychiatry Res 1980; 3: 75–83

    Article  CAS  PubMed  Google Scholar 

  12. Fils-Aime ML, Eckardt MJ, George DT, Brown GL, Mefford I, Linnoila M . Early-onset alcoholics have lower cerebrospinal fluid 5-hydroxyindoleacetic acid levels than late-onset alcoholics Arch Gen Psychiatry 1996; 53: 211–216

    Article  CAS  PubMed  Google Scholar 

  13. Ogilvie AD, Battersby S, Bubb VJ, Fink G, Harmar AJ, Goodwin GM et al. Polymorphism in serotonin transporter gene associated with susceptibility to major depression Lancet 1996; 347: 731–733

    Article  CAS  PubMed  Google Scholar 

  14. Nakhai B, Nielsen DA, Linnoila M, Goldman D . Two naturally occurring amino acid substitutions in the human 5-HT1A receptor: glycine 22 to serine 22 and isoleucine 28 to valine 28 Biochem Biophys Res Commun 1995; 16: 530–536

    Article  Google Scholar 

  15. Ozaki N, Rosenthal NE, Pesonen U, Lappalainen J, Feldman-Naim S, Schwartz PJ et al. Two naturally occurring amino acid substitutions of the 5-HT2A receptor: similar prevalence in patients with seasonal affective disorder and controls Biol Psychiatry 1996; 40: 1267–1272

    Article  CAS  PubMed  Google Scholar 

  16. Lappalainen J, Zhang L, Dean M, Oz M, Ozaki N, Yu DH et al. Identification, expression, and pharmacology of a Cys23-Ser23 substitution in the human 5-HT2c receptor gene (HTR2C) Genomics 1995; 27: 274–279

    Article  CAS  PubMed  Google Scholar 

  17. Hotamisligil GS, Breakefield XO . Human monoamine oxydase A gene determines levels of enzyme activity Am J Hum Genet 1991; 49: 383–392

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Konradi C, Ozelius L, Breakefield XO . Highly polymorphic (GT)n repeat sequence in intron II of the human MAOB gene Genomics 1992; 12: 176–177

    Article  CAS  PubMed  Google Scholar 

  19. Nielsen DA, Jenkins GL, Stefanisko KM, Jefferson KK, Goldman D . Sequence, splice site and population frequency distribution analyses of the polymorphic human tryptophan hydroxylase intron 7 Mol Brain Res 1997; 45: 145–148

    Article  CAS  PubMed  Google Scholar 

  20. Nielsen DA, Goldman D, Virkkunen M, Tokola R, Rawlings R, Linnoila M . Suicidality and 5-hydroxyindoleacetic acid concentration associated with a tryptophan hydroxylase polymorphism Arch Gen Psychiatry 1994; 51: 34–38

    Article  CAS  PubMed  Google Scholar 

  21. Nielsen DA, Virkkunen M, Lappalainen J, Eggert M, Brown GL, Long JC et al. A tryptophan hydroxylase gene marker for suicidality and alcoholism Arch Gen Psychiatry 1998; 55: 593–602

    Article  CAS  PubMed  Google Scholar 

  22. Mann JJ, Malone KM, Nielsen DA, Goldman D, Erdos J, Gelernter J . Possible association of a polymorphism of the tryptophan hydroxylase gene with suicidal behaviour in depressed patients Am J Psychiatry 1997; 154: 1451–1453

    Article  CAS  PubMed  Google Scholar 

  23. New AS, Gelernter J, Yovell Y, Trestman RL, Nielsen DA, Silverman J et al. Tryptophan hydroxylase genotype is associated with impulsive-aggression measures: a preliminary study Am J Med Genet 1998; 81: 13–17

    Article  CAS  PubMed  Google Scholar 

  24. Hsu YP, Tai JJ, Seow SV, Chen CC, Yu JM, Cheng AT . Allelic association of tryptophan hydroxylase with alcoholism in five Taiwanese ethnic groups Mol Psychiatry 1998; 3: 213–214

    Article  CAS  PubMed  Google Scholar 

  25. Bellivier F, Leboyer M, Courtet P, Buresi C, Beaufils B, Samolyk D et al. Association between the tryptophan hydroxylase gene and manic-depressive illness Arch Gen Psychiatry 1998; 55: 33–37

    Article  CAS  PubMed  Google Scholar 

  26. Furlong RA, Ho L, Rubinsztein JS, Walsh C, Paykel ES, Rubinsztein DC . No association of the tryptophan hydroxylase gene with bipolar affective disorder, unipolar affective disorder, or suicidal behaviour in major affective disorder Am J Med Genet 1998; 81: 245–247

    Article  CAS  PubMed  Google Scholar 

  27. McQuillin A, Lawrence J, Kalsi G, Chen A, Gurling H, Curtis D . No allelic association between bipolar affective disorder and the tryptophan hydroxylase gene Arch Gen Psychiatry 1999; 56: 99–101

    Article  CAS  PubMed  Google Scholar 

  28. Manuck SB, Flory JD, Ferrell RE, Dent KM, Mann JJ, Muldoon MF . Aggression and anger-related traits associated with a polymorphism of the tryptophan hydroxylase gene Biol Psychiatry 1999; 45: 603–614

    Article  CAS  PubMed  Google Scholar 

  29. Rotondo A, Mazzanti CM, Nielsen DA, Schuebel KE, Lezza A, Gemignani A et al. Lack of association of promoter region variation in tryptophan hydroxylase and serotonin transporter with obsessive compulsive disorder and eating disorders Neuropsychiatric Genet 1997; 21: 621, A146

    Google Scholar 

  30. Nurnberger JI Jr, Bleha MC, Kaufmann CA, York-Cooler C, Simpson SG, Harkavy-Friedman J et al. Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative Arch Gen Psychiatry 1994; 51: 849–859

    Article  PubMed  Google Scholar 

  31. Hongyo T, Buzard G, Calvert R, Weghorst C . ‘Cold SSCP’: a simple, rapid and non-radioactive method for optimized single-strand conformation polymorphism analyses Nucleic Acids Res 1993; 21: 3637–3642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Oudet C, Heilig R, Hanauer A, Mandel JL . Non radioactive assay for new microsatellite polymorphisms at the 5′ end of dystrophin gene, and estimation of intragenic recombination Am J Hum Genet 1991; 49: 311–319

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Terwilliger JD, Ott J . Handbook of Human Genetic Linkage Johns Hopkins University Press, Baltimore 1994

    Google Scholar 

  34. Han L, Nielsen DA, Rosenthal NE, Jefferson K, Kaye W, Murphy D et al. No coding variant of the tryptophan hydroxylase gene detected in seasonal affective disorder, obsessive-compulsive disorder, anorexia nervosa, and alcoholism Biol Psychiatry 1999; 45: 615–619

    Article  CAS  PubMed  Google Scholar 

  35. Heils A, Teufel A, Petri S, Stober G, Riederer P, Bengel D et al. Allelic variation of human serotonin transporter gene expression J Neurochem 1996; 66: 2621–2624

    Article  CAS  PubMed  Google Scholar 

  36. Teerawatanasuk N, Carr LG . CBF/NF-Y activates transcription of the human tryptophan hydroxylase gene through an inverted CCAAT box Mol Brain Res 1998; 55: 61–70

    Article  CAS  PubMed  Google Scholar 

  37. Krawczak M, Reiss J, Cooper DN . The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences Hum Genet 1992; 90: 41–54

    Article  CAS  PubMed  Google Scholar 

  38. Reed R . Initial splice-site recognition and pairing during pre-mRNA splicing Curr Opin Genet Dev 1996; 6: 215–220

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Drs M Leboyer, F Bellivier, M Preisig and J Golaz for recruitment of subjects. This research was supported by grants 32-47315.96 and 31-53849.98 from the Fond National de la Recherche Suisse. APG was supported by Rhône-Poulenc-Rorer.

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Correspondence to C Buresi.

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Paoloni-Giacobino, A., Mouthon, D., Lambercy, C. et al. Identification and analysis of new sequence variants in the human tryptophan hydroxylase (TpH) gene. Mol Psychiatry 5, 49–55 (2000). https://doi.org/10.1038/sj.mp.4000647

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