@article{8dfaae9451c1455e8d8af494487005c4,
title = "A functional alternative splicing mutation in human tryptophan hydroxylase-2",
abstract = "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.",
keywords = "SNP, TPH2, alternative splicing, serotonin (5-HT)",
author = "X. Zhang and Nicholls, {P. J.} and G. Laje and Sotnikova, {T. D.} and Gainetdinov, {R. R.} and Albert, {P. R.} and G. Rajkowska and Stockmeier, {C. A.} and Speer, {M. C.} and Steffens, {D. C.} and Austin, {M. C.} and McMahon, {F. J.} and Krishnan, {K. R.R.} and Garcia-Blanco, {M. A.} and Caron, {M. G.}",
note = "Funding Information: The authors would like to dedicate this paper to the memory of our esteemed colleague Dr Marcy C. Speer who passed away in 2008. This study was funded in part by the Intramural Research Program of the National Institute of Mental Health, NIH. The content of this publication does not necessarily reflect the views or policies of the DHHS, nor does mention of trade names, commercial products, or organizations imply endorsement by the United States Government. We thank the National Institute of Mental Health (NIMH) Center for Collaborative Genetic Studies on Mental Disorders. Specific acknowledgement is given for STAR*D research team in performing the clinical study and gathering the DNA samples. We deeply appreciate the assistance of the next-of-kin of the deceased, and gratefully acknowledge the support of Elizabeth K Balraj, MD, and the staff of the Cuyahoga County Coroner{\textquoteright}s Office, Cleveland, OH, USA, for access to postmortem brain samples. We gratefully acknowledge Lisa Konick and Lesa Dieter and Drs James C Overholser, George Jurjus and Herbert Y Meltzer for psychiatric assessments of the subjects. We also thank Ava Sweeney, Xiuqin Zhang (M.G.C. lab), David Mauger (M.A.G-B. lab), Dhanrajan Tiruchinapalli (Jack Keene laboratory, Duke), Liang Kee Goh, Sharon O{\textquoteright}Neill and King Shung Khoo (Duke-NUS) for their laboratory technical assistance and advice. We also acknowledge the advice and helpful discussion of Drs Allison Ashley-Koch (Duke), John Rush and Steve Rosen (Duke-NUS). This work was supported in part by National Institutes of Health Grants MH079201 (M.G.C), MH060451 (K.R.R.K.), MH067996 (C.A.S.), RR017701 (C.A.S., G.R.), Singapore National Medical Research Council Translational and Clinical Research Program NMRC/ TCR/003-GMS/2008 (X.Z and M.G.C.), Singapore Ministry of Education T208A3126 (X.Z.), NARSAD Distinguished Investigator Award (M.G.C.), NARSAD Young Investigator Award (X.Z.), The Lennon Family Foundation (M.G.C.), the Canadian research funds from CIHR, CPRF and AstraZeneca (P.R.A.).",
year = "2011",
month = dec,
doi = "10.1038/mp.2010.99",
language = "English (US)",
volume = "16",
pages = "1169--1176",
journal = "Molecular Psychiatry",
issn = "1359-4184",
publisher = "Springer Nature",
number = "12",
}