Neuron. 2005 Jan 6;45(1):11-6.

Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression.

Zhang X, Gainetdinov RR, Beaulieu JM, Sotnikova TD, Burch LH, Williams RB, Schwartz DA, Krishnan KR, Caron MG.

Source

Department of Cell Biology, Center for Models of Human Disease, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC 27710, USA.

Abstract

Dysregulation of central serotonin neurotransmission has been widely suspected as an important contributor to major depression. Here, we identify a (G1463A) single nucleotide polymorphism (SNP) in the rate-limiting enzyme of neuronal serotonin synthesis, human tryptophan hydroxylase-2 (hTPH2). The functional SNP in hTPH2 replaces the highly conserved Arg441 with His, which results in approximately 80% loss of function in serotonin production when hTPH2 is expressed in PC12 cells. Strikingly, SNP analysis in a cohort of 87 patients with unipolar major depression revealed that nine patients carried the mutant (1463A) allele, while among 219 controls, three subjects carried this mutation. In addition, this functional SNP was not found in a cohort of 60 bipolar disorder patients. Identification of a loss-of-function mutation in hTPH2 suggests that defect in brain serotonin synthesis may represent an important risk factor for unipolar major depression.

Comment in

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]
Response to Zhang et al. (2005): loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 45, 11-16.Glatt CE, Carlson E, Taylor TR, Risch N, Reus VI, Schaefer CA. Neuron. 2005 Dec 8; 48(5):704-5; author reply 705-6.
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]
Response to Zhang et al. (2005): loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 45, 11-16.Zhou Z, Peters EJ, Hamilton SP, McMahon F, Thomas C, McGrath PJ, Rush J, Trivedi MH, Charney DS, Roy A, et al. Neuron. 2005 Dec 8; 48(5):702-3; author reply 705-6.
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]
Response to Zhang et al (2005): loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major Depression. Neuron 45, 11-16.Van Den Bogaert A, De Zutter S, Heyrman L, Mendlewicz J, Adolfsson R, Van Broeckhoven C, Del-Favero J. Neuron. 2005 Dec 8; 48(5):704; author reply 705-6.
Overview: a rare opportunity or just one less reason to be depressed. [Neuron. 2005]
Overview: a rare opportunity or just one less reason to be depressed.Blakely RD. Neuron. 2005 Dec 8; 48(5):701-2; author reply 705-6.

PMID:: 15629698; [PubMed - indexed for MEDLINE]

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