Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report a possible association between autism in our sample and a recently described brain-expressed tryptophan hydroxylase gene (TPH2). The well-replicated involvement of the serotonin neurotransmitter system in autism has stimulated interest in many genes in the serotonin pathway as possible candidates for mutations leading to autism susceptibility. Serotonin synthesis is controlled by the rate-limiting enzyme tryptophan hydroxylase. A mouse study of the original tryptophan hydroxylase gene (TPH1) and the new isoform (TPH2) showed that while TPH1 is primarily expressed peripherally, TPH2 is found exclusively in brain tissue. We searched for human sequence variants in 6,467 nucleotides covering all 11 exons of TPH2, and also 248 nucleotides upstream of the start codon, and 935 nucleotides downstream of the stop codon. Eighteen variants were characterized in 88 subjects with autism studied at our two centers, and 95 unrelated control subjects. Using a model-free association method and empirical P value estimation, two variants showed frequency differences between autism and control subjects (P = 0.01 for a T-G variant in intron 1, and P = 0.02 for a A-T variant in intron 4). A haplotype including these variants showed slightly increased significance (P = 0.005). Further investigation of clinical phenotypes showed a possible association between presence of the variants at these two SNPs and higher scores on the Autism Diagnostic Interview (ADI) domain describing repetitive and stereotyped behaviors (P = 0.007). We conclude that TPH2 may play a modest role in autism susceptibility, perhaps relating specifically to repetitive behaviors, pending replication of this result.
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PMID:Possible association between autism and variants in the brain-expressed tryptophan hydroxylase gene (TPH2). 1576 92

The TPH1 and TPH2 genes encode the rate-limiting enzymes that control serotonin biosynthesis, and serotonin is clearly altered in autism. In the current study, eight SNPs in the TPH1 gene region and eight SNPs within the TPH2 gene were examined by family-based association tests in a large cohort of 352 families with autism and in clinically defined subsets of these families with either severe obsessive-compulsive behaviors (sOCB) or self-stimulatory behaviors (SSB). We found no evidence for association between autism and single SNPs or haplotypes of the TPH1 and TPH2 genes in the cohort of all families or in the sOCB and SSB subsets. In particular, we failed to replicate the association between autism and variants of the TPH2 gene, rs4341581 (TRANSMIT P = 1; PDT P = 0.323; FBAT P = 0.446) and rs11179000 (TRANSMIT P = 0.174; PDT P = 0.293; FBAT P = 0.374). Furthermore, no evidence for linkage was observed between autism and SNPs in the TPH1 and TPH2 genes (although linkage at the TPH2 locus was observed in the SSB subset). Thus, it appears unlikely that the TPH1 and TPH2 genes play a significant role in the susceptibility to autism or to autism endophenotypes including sOCB and SSB.
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PMID:Family-based association study of TPH1 and TPH2 polymorphisms in autism. 1695 27

Autism is a neurodevelopmental disorder of unclear etiology. The consistent finding of platelet hyperserotonemia in a proportion of patients and its heritability within affected families suggest that genes involved in the serotonin system play a role in this disorder. The role in autism etiology of seven candidate genes in the serotonin metabolic and neurotransmission pathways and mapping to autism linkage regions (SLC6A4, HTR1A, HTR1D, HTR2A, HTR5A, TPH1 and ITGB3) was analyzed in a sample of 186 nuclear families. The impact of interactions among these genes in autism was assessed using the multifactor-dimensionality reduction (MDR) method in 186 patients and 181 controls. We further evaluated whether the effect of specific gene variants or gene interactions associated with autism etiology might be mediated by their influence on serotonin levels, using the quantitative transmission disequilibrium test (QTDT) and the restricted partition method (RPM), in a sample of 109 autistic children. We report a significant main effect of the HTR5A gene in autism (P = 0.0088), and a significant three-locus model comprising a synergistic interaction between the ITGB3 and SLC6A4 genes with an additive effect of HTR5A (P < 0.0010). In addition to the previously reported contribution of SLC6A4, we found significant associations of ITGB3 haplotypes with serotonin level distribution (P = 0.0163). The most significant models contributing to serotonin distribution were found for interactions between TPH1 rs4537731 and SLC6A4 haplotypes (P = 0.002) and between HTR1D rs6300 and SLC6A4 haplotypes (P = 0.013). In addition to the significant independent effects, evidence for interaction between SLC6A4 and ITGB3 markers was also found. The overall results implicate SLC6A4 and ITGB3 gene interactions in autism etiology and in serotonin level determination, providing evidence for a common underlying genetic mechanism and a molecular explanation for the association of platelet hyperserotonemia with autism.
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PMID:Evidence for epistasis between SLC6A4 and ITGB3 in autism etiology and in the determination of platelet serotonin levels. 1720 4

Elevated platelet serotonin (5-hydroxytryptamine, 5-HT) is found in a subset of children with autism and in some of their first-degree relatives. Indices of the platelet serotonin system, including whole blood 5-HT, 5-HT binding affinity for the serotonin transporter (K(m)), 5-HT uptake (V(max)), and lysergic acid diethylamide (LSD) receptor binding, were previously studied in 24 first-degree relatives of probands with autism, half of whom were selected for elevated whole blood 5-HT levels. All subjects were then genotyped for selected polymorphisms at the SLC6A4, HTR7, HTR2A, ITGB3, and TPH1 loci. Previous studies allowed an a priori prediction of SLC6A4 haplotypes that separated the subjects into three groups that showed significantly different 5-HT binding affinity (K(m), p=0.005) and 5-HT uptake rate (V(max), p=0.046). Genotypes at four individual polymorphisms in SLC6A4 were not associated with platelet 5-HT indices. Haplotypes at SLC6A4 and individual genotypes of polymorphisms at SLC6A4, HTR7, HTR2A, ITGB3, and TPH1 showed no significant association with whole blood 5-HT. Haplotype analysis of two polymorphisms in TPH1 revealed a nominally significant association with whole blood 5-HT (p=0.046). These initial studies of indices of the 5-HT system with several single-nucleotide polymorphisms at loci in this system generate hypotheses for testing in other samples.
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PMID:Molecular genetics of the platelet serotonin system in first-degree relatives of patients with autism. 1740 48

Serotonin and vitamin D have been proposed to play a role in autism; however, no causal mechanism has been established. Here, we present evidence that vitamin D hormone (calcitriol) activates the transcription of the serotonin-synthesizing gene tryptophan hydroxylase 2 (TPH2) in the brain at a vitamin D response element (VDRE) and represses the transcription of TPH1 in tissues outside the blood-brain barrier at a distinct VDRE. The proposed mechanism explains 4 major characteristics associated with autism: the low concentrations of serotonin in the brain and its elevated concentrations in tissues outside the blood-brain barrier; the low concentrations of the vitamin D hormone precursor 25-hydroxyvitamin D [25(OH)D3]; the high male prevalence of autism; and the presence of maternal antibodies against fetal brain tissue. Two peptide hormones, oxytocin and vasopressin, are also associated with autism and genes encoding the oxytocin-neurophysin I preproprotein, the oxytocin receptor, and the arginine vasopressin receptor contain VDREs for activation. Supplementation with vitamin D and tryptophan is a practical and affordable solution to help prevent autism and possibly ameliorate some symptoms of the disorder.
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PMID:Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism. 2455 99