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.
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA. xiaodong.zhang@duke-nus.edu.sg
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: P J
authors.initials: PJ
authors.lastname: Nicholls
authors.forename: G
authors.initials: G
authors.lastname: Laje
authors.forename: T D
authors.initials: TD
authors.lastname: Sotnikova
authors.forename: R R
authors.initials: RR
authors.lastname: Gainetdinov
authors.forename: P R
authors.initials: PR
authors.lastname: Albert
authors.forename: G
authors.initials: G
authors.lastname: Rajkowska
authors.forename: C A
authors.initials: CA
authors.lastname: Stockmeier
authors.forename: M C
authors.initials: MC
authors.lastname: Speer
authors.forename: D C
authors.initials: DC
authors.lastname: Steffens
authors.forename: M C
authors.initials: MC
authors.lastname: Austin
authors.forename: F J
authors.initials: FJ
authors.lastname: McMahon
authors.forename: K R R
authors.initials: KR
authors.lastname: Krishnan
authors.forename: M A
authors.initials: MA
authors.lastname: Garcia-Blanco
authors.forename: M G
authors.initials: MG
authors.lastname: Caron
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001933:Brain Stem / Q000378:metabolism; D002461:Cell Line, Transformed; D003863:Depression / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics* / Q000523:psychology; D005838:Genotype; D006801:Humans; D008297:Male; D016716:PC12 Cells; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D051381:Rats; D012701:Serotonin / Q000096:biosynthesis*; D014365:Tryptophan Hydroxylase / Q000235:genetics*
chemical_list: D012701:Serotonin; C494784:TPH2 protein, human; D014365:Tryptophan Hydroxylase