CONTEXT: Exposure to adverse events during prenatal and postnatal development, as well as serotonin deficiency, have been implicated in disturbances of mood and impulsivity, but the underlying mechanisms are unknown. OBJECTIVE: To investigate the long-term effects of an impaired serotonin synthesis on the developing human brain, we studied the effects of nonsynonymous mutations affecting tryptophan hydroxylase (TPH) enzymes responsible for serotonin production in maternal reproductive tissues (TPH1) and the brain (TPH2). DESIGN: Family-based case-control and functional studies of candidate genes. SETTING: Adult outpatients with attention-deficit/hyperactivity disorder (ADHD), their family members, and random control subjects were recruited across Norway. PARTICIPANTS: Nine pedigrees with TPH1 and TPH2 mutation carriers were identified among 459 patients with ADHD and 187 controls. The TPH genes were then sequenced in 97 additional family members, and information about psychiatric diagnoses and symptoms was obtained from 606 controls, the 459 patients, and their relatives. MAIN OUTCOME MEASURES: The effects of maternal vs paternal TPH1 mutations compared in all families. RESULTS: Nine different TPH1 and TPH2 mutations were found by sequencing in 646 individuals (1.0% and 0.2% allele frequency, respectively). In vitro studies showed that 8 TPH mutants had significantly impaired enzyme function. Family analysis of 38 TPH1 mutation carriers and 41 of their offspring revealed that offspring of mothers carrying TPH1 mutations reported 1.5- to 2.5-times-higher ADHD scores and related symptoms during childhood and as adults than did controls (P < 10(-6)) or offspring of fathers with the corresponding TPH1 mutations (P < .001). CONCLUSIONS: Impaired maternal serotonin production may have long-term consequences for brain development and increase the risk of ADHD-related symptoms and behavior in offspring. Replication studies are required to form conclusions about the clinical implications of mutations affecting serotonin biosynthesis.
CONTEXT: Exposure to adverse events during prenatal and postnatal development, as well as serotonin deficiency, have been implicated in disturbances of mood and impulsivity, but the underlying mechanisms are unknown. OBJECTIVE: To investigate the long-term effects of an impaired serotonin synthesis on the developing human brain, we studied the effects of nonsynonymous mutations affecting tryptophan hydroxylase (TPH) enzymes responsible for serotonin production in maternal reproductive tissues (TPH1) and the brain (TPH2). DESIGN: Family-based case-control and functional studies of candidate genes. SETTING: Adult outpatients with attention-deficit/hyperactivity disorder (ADHD), their family members, and random control subjects were recruited across Norway. PARTICIPANTS: Nine pedigrees with TPH1 and TPH2 mutation carriers were identified among 459 patients with ADHD and 187 controls. The TPH genes were then sequenced in 97 additional family members, and information about psychiatric diagnoses and symptoms was obtained from 606 controls, the 459 patients, and their relatives. MAIN OUTCOME MEASURES: The effects of maternal vs paternal TPH1 mutations compared in all families. RESULTS: Nine different TPH1 and TPH2 mutations were found by sequencing in 646 individuals (1.0% and 0.2% allele frequency, respectively). In vitro studies showed that 8 TPH mutants had significantly impaired enzyme function. Family analysis of 38 TPH1 mutation carriers and 41 of their offspring revealed that offspring of mothers carrying TPH1 mutations reported 1.5- to 2.5-times-higher ADHD scores and related symptoms during childhood and as adults than did controls (P < 10(-6)) or offspring of fathers with the corresponding TPH1 mutations (P < .001). CONCLUSIONS: Impaired maternal serotonin production may have long-term consequences for brain development and increase the risk of ADHD-related symptoms and behavior in offspring. Replication studies are required to form conclusions about the clinical implications of mutations affecting serotonin biosynthesis.
Authors: William B Siesser; Benjamin D Sachs; Amy J Ramsey; Tatyana D Sotnikova; Jean-Martin Beaulieu; Xiaodong Zhang; Marc G Caron; Raul R Gainetdinov Journal: ACS Chem Neurosci Date: 2012-10-01 Impact factor: 4.418
Authors: B Franke; S V Faraone; P Asherson; J Buitelaar; C H D Bau; J A Ramos-Quiroga; E Mick; E H Grevet; S Johansson; J Haavik; K-P Lesch; B Cormand; A Reif Journal: Mol Psychiatry Date: 2011-11-22 Impact factor: 15.992
Authors: Emma Mitchell; Shifra L Klein; Kimon V Argyropoulos; Ali Sharma; Robin B Chan; Judit Gal Toth; Luendreo Barboza; Charlotte Bavley; Analia Bortolozzi; Qiuying Chen; Bingfang Liu; Joanne Ingenito; Willie Mark; Jarrod Dudakov; Steven Gross; Gilbert Di Paolo; Francesc Artigas; Marcel van den Brink; Miklos Toth Journal: Nat Commun Date: 2016-05-13 Impact factor: 14.919
Authors: Georgette L Suidan; Daniel Duerschmied; Gregory M Dillon; Veronique Vanderhorst; Thomas G Hampton; Siu Ling Wong; Jaymie R Voorhees; Denisa D Wagner Journal: PLoS One Date: 2013-03-14 Impact factor: 3.240