A functional alternative splicing mutation in human tryptophan hydroxylase-2

被引：23

作者：

Zhang, X. ^{[1
,2
,3
]}

Nicholls, P. J. ^{[3
]}

Laje, G. ^{[4
]}

Sotnikova, T. D. ^{[2
,5
]}

Gainetdinov, R. R. ^{[2
,5
]}

Albert, P. R. ^{[6
]}

Rajkowska, G. ^{[7
]}

Stockmeier, C. A. ^{[7
,8
]}

Speer, M. C. ^{[9
]}

Steffens, D. C. ^{[3
]}

Austin, M. C. ^{[7
]}

McMahon, F. J. ^{[4
]}

Krishnan, K. R. R. ^{[3
]}

Garcia-Blanco, M. A. ^{[10
]}

Caron, M. G. ^{[2
]}

机构：

[1] Duke Natl Univ Singapore, Grad Sch Med, Neurosci & Behav Disorders Program, Singapore 169857, Singapore

[2] Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA

[3] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC USA

[4] NIMH, Unit Genet Basis Mood & Anxiety Disorders, NIH, Bethesda, MD 20892 USA

[5] Italian Inst Technol, Dept Neurosci, Genoa, Italy

[6] Univ Ottawa, OHRI Neurosci, Ottawa, ON, Canada

[7] Univ Mississippi, Med Ctr, Dept Psychiat & Human Behav, Jackson, MS 39216 USA

[8] Case Western Reserve Univ, Dept Psychiat, Cleveland, OH 44106 USA

[9] Duke Univ, Med Ctr, Ctr Human Genet, Durham, NC USA

[10] Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC USA

来源：

MOLECULAR PSYCHIATRY | 2011年 / 16卷 / 12期

基金：

美国国家卫生研究院; 英国医学研究理事会;

关键词：

TPH2; serotonin (5-HT); SNP; alternative splicing; HUMAN TRYPTOPHAN-HYDROXYLASE-2 GENE; BIPOLAR AFFECTIVE-DISORDER; OF-FUNCTION MUTATION; MAJOR DEPRESSION; SUICIDAL-BEHAVIOR; COMORBID DEPRESSION; REGULATORY REGION; SEROTONIN; DISEASE; ASSOCIATION;

D O I：

10.1038/mp.2010.99

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The brain serotonergic system has an essential role in the physiological functions of the central nervous system and dysregulation of serotonin (5-HT) homeostasis has been implicated in many neuropsychiatric disorders. The tryptophan hydroxylase-2 (TPH2) gene is the rate-limiting enzyme in brain 5-HT synthesis, and thus is an ideal candidate gene for understanding the role of dysregulation of brain serotonergic homeostasis. Here, we characterized a common, but functional single-nucleotide polymorphism (SNP rs1386493) in the TPH2 gene, which decreases efficiency of normal RNA splicing, resulting in a truncated TPH2 protein (TPH2-TR) by alternative splicing. TPH2-TR, which lacks TPH2 enzyme activity, dominant-negatively affects full-length TPH2 function, causing reduced 5-HT production. The predicted mRNA for TPH2-TR is present in postmortem brain of rs1386493 carriers. The rs13864923 variant does not appear to be overrepresented in either global or multiplex depression cohorts. However, in combination with other gene variants linked to 5-HT homeostasis, this variant may exhibit important epistatic influences. Molecular Psychiatry (2011) 16, 1169-1176; doi:10.1038/mp.2010.99; published online 21 September 2010

引用

页码：1169 / 1176

页数：8

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