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)

Evidence implicates the serotonin transporter gene (SLC6A4) and the 15q11-q13 genes as candidates for autism as well as restricted repetitive behavior (RRB). We conducted dense transmission disequilibrium mapping of the 15q11-q13 region with 93 single nucleotide polymorphisms (SNPs) in 86 strictly defined autism trios and tested association between SNPs and autism using the transmission disequilibrium test (TDT). As exploratory analyses, parent-of-origin effects were examined using likelihood-ratio tests (LRTs) and genotype-phenotype associations for specific RRB using the Family-Based Association Test (FBAT). Additionally, gene-gene interactions between nominally associated 15q11-q13 variants and 5-HTTLPR, the common length polymorphism of SLC6A4, were examined using conditional logistic regression (CLR). TDT revealed nominally significant transmission disequilibrium between autism and five SNPs, three of which are located within close proximity of the GABA(A) receptor subunit gene clusters. Three SNPs in the SNRPN/UBE3A region had marginal imprinting effects. FBAT for genotype-phenotype relations revealed nominally significant association between two SNPs and one ADI-R subdomain item. However, both TDT and FBAT were not statistically significant after correcting for multiple comparisons. Gene-gene interaction analyses by CLR revealed additive genetic effect models, without interaction terms, fit the data best. Lack of robust association between the 15q11-q13 SNPs and RRB phenotypes may be due to a small sample size and absence of more specific RRB measurement. Further investigation of the 15q11-q13 region with denser genotyping in a larger sample set may be necessary to determine whether this region confers risk to autism, indicated by association, or to specific autism phenotypes.
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PMID:Transmission disequilibrium testing of the chromosome 15q11-q13 region in autism. 1836 19

Increased platelet serotonin level (PSL) has been consistently found in a portion of autistic patients. Suggested mechanisms for hyperserotonemia in autism have been increased synthesis of serotonin (5HT) by tryptophan hydroxylase (TPH), increased uptake into platelets through 5HT transporter (5HTt), diminished release from platelets through 5HT2A receptor (5HT2Ar) and decreased metabolism by monoamine oxydase (MAOA). The allelic influence of genes, encoding the mentioned 5HT elements, on PSL was investigated in 63 autistic subjects. Our study shows that 5HTt-LPR and -1438AG 5HT(2Ar) genotypes did not significantly affect PSL. However, significantly higher PSLs were observed in subjects with "cc" genotype of a218c TPH and subjects with "4" genotype of uVNTR MAOA. In addition, when TPH-cc and MAOA-4 were combined as "high 5HT" genotypes, a correlative increase in PSL was observed with the increase in the number of "high 5HT" genotypes. These results suggest a possible synergistic effect of genes regulating 5HT synthesis/degradation in dysregulation of the peripheral 5HT homeostasis of autistic patients.
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PMID:Hyperserotonemia in autism: the potential role of 5HT-related gene variants. 1840 62

Autism is a pervasive developmental disorder diagnosed in early childhood. Abnormalities of serotonergic neurotransmission have been reported in autism. Serotonin transporter (5-HTT), which modulates serotonin levels, is a major therapeutic target in autism. Therefore, factors that regulate 5-HTT expression might be implicated in autism. One candidate 5-HTT-regulatory protein is the presynaptic protein, syntaxin 1A (STX1A). We examined the association of STX1A with autism in a trio association study using DNA samples from 249 AGRE trios with autistic probands. Only male probands were selected, since autism is more prevalent among males. The probands of 102 trios had IQ>70, and were considered as high functioning autism (HFA). In transmission disequilibrium test (TDT) analysis, rs2293485 (p=0.034) and rs4717806 (p=0.033) showed nominal associations with HFA; modest haplotype association was also observed. The SNPs that showed associations were related to early developmental abnormalities (ADI-R_D). We further compared STX1A mRNA expression in the lymphocytes of drug-naive HFA patients (n=12) and age- and sex-matched controls (n=13). STX1A expression in the HFA group was significantly higher (p=0.001) than that of controls. Thus, we suggest a possible role of STX1A in the pathogenesis of HFA. During early childhood, there is a period of high brain serotonin synthesis that is disrupted in autistic children; STX1A might influence the serotonergic system during this stage of neurodevelopment, as implied by the association with ADI-R_D.
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PMID:Genetic and expression analyses reveal elevated expression of syntaxin 1A ( STX1A) in high functioning autism. 1859 6

Serotoninergic dysfunction is highly implicated in autism. Serotonin transporter gene (SLC6A4) that regulates synaptic serotonin level has been investigated as a candidate gene for autism, but consensus opinion on possible association is still lacking. Converging evidences of platelet-hyperserotoninemia in approximately 25% of the patients, betterment of ritualistic behavior on administration of SSRI and linkage to chromosome 17q11 harboring SLC6A4, supports the hypothesis that SLC6A4 polymorphisms may contribute towards autism pathology. Our recent report on 5-HTTLPR marker represents the first study on genetic association of SLC6A4 with autism in the Indian population. Further analysis involving additional markers may reinforce the earlier hypothesis. So in the present study, we have investigated the association of a VNTR of 17 bp at intron2 (STin2) and an SNP at 3'UTR (HTT-3'UTR-SNP) of the gene with autism using family and population-based approaches. We have genotyped 421 individuals (93 autistic subjects, their parents and 160 controls) and consistent with other publications, family-based association studies using individual markers (STin2 and HTT-3'UTR-SNP) have not revealed any preferential allelic transmission to the probands. However, the interesting finding of strong linkage disequilibrium (LD) between the markers and significant disease-specific distortion in the distribution of HTT-3'UTR-SNP genotypes (T1chi(2)=5.19, P=0.02; OR=2.89, 95% CI=1.13-7.41) and the specific haplotypes of the two markers (LRS=11.85, p(c)=0.02), with higher frequencies of T/T genotype and 10-T haplotype in autistic cases suggests that either these markers or nearby markers of SLC6A4 that are in LD, may pose a risk towards autism in the Eastern Indian population.
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PMID:Population-based association study and contrasting linkage disequilibrium pattern reveal genetic association of SLC6A4 with autism in the Indian population from West Bengal. 1880 97

Rare, functional, non-synonymous variants in the human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT) gene (SLC6A4) have been identified in both autism and obsessive-compulsive disorder (OCD). Within autism, rare hSERT coding variants associate with rigid-compulsive traits, suggesting both phenotypic overlap with OCD and a shared relationship with disrupted 5-HT signalling. Here, we document functional perturbations of three of these variants: Ile425Leu; Phe465Leu; and Leu550Val. In transiently transfected HeLa cells, the three variants confer a gain of 5-HT transport phenotype. Specifically, enhanced SERT activity was also observed in lymphoblastoid lines derived from mutation carriers. In contrast to previously characterized Gly56Ala, where increased transport activity derives from catalytic activation, the three novel variants exhibit elevated surface density as revealed through both surface antagonist-binding and biotinylation studies. Unlike Gly56Ala, mutants Ile425Leu, Phe465Leu and Leu550Val retain a capacity for acute PKG and p38 MAPK regulation. However, both Gly56Ala and Ile425Leu demonstrate markedly reduced sensitivity to PP2A antagonists, suggesting that deficits in trafficking and catalytic modulation may derive from a common basis in perturbed phosphatase regulation. When expressed stably from the same genomic locus in CHO cells, both Gly56Ala and Ile425Leu display catalytic activation, accompanied by a striking loss of SERT protein.
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PMID:Enhanced activity of human serotonin transporter variants associated with autism. 1895 75

The human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT, SLC6A4) figures prominently in the etiology and treatment of many prevalent neurobehavioral disorders including anxiety, alcoholism, depression, autism, and obsessive-compulsive disorder (OCD). Here, we use naturally occurring polymorphisms in recombinant inbred (RI) lines to identify multiple phenotypes associated with altered SERT function. The widely used mouse strain C57BL/6J, harbors a SERT haplotype defined by 2 nonsynonymous coding variants [Gly-39 and Lys-152 (GK)]. At these positions, many other mouse lines, including DBA/2J, encode, respectively, Glu-39 and Arg-152 (ER haplotype), amino acids found also in hSERT. Ex vivo synaptosomal 5-HT transport studies revealed reduced uptake associated with the GK variant, a finding confirmed by in vitro heterologous expression studies. Experimental and in silico approaches using RI lines (C57BL/6J x DBA/2J = BXD) identify multiple anatomical, biochemical, and behavioral phenotypes specifically impacted by GK/ER variation. Among our findings are several traits associated with alcohol consumption and multiple traits associated with dopamine signaling. Further bioinformatic analysis of BXD phenotypes, combined with biochemical evaluation of SERT knockout mice, nominates SERT-dependent 5-HT signaling as a major determinant of midbrain iron homeostasis that, in turn, dictates iron-regulated DA phenotypes. Our studies provide an example of the power of coordinated in vitro, in vivo, and in silico approaches using mouse RI lines to elucidate and quantify the system-level impact of gene variation.
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PMID:Functional coding variation in recombinant inbred mouse lines reveals multiple serotonin transporter-associated phenotypes. 1917 83

Disturbances in serotonin (5HT) neurotransmission have been indicated as biological substrates in several neuropsychiatric disorders including autism. Blood 5HT concentrations, elevated in about one-third of autistic subjects, are regulated through the action of peripheral 5HT-associated proteins. We have measured the activity of two platelet 5HT-associated proteins: 5HT transporter (5HTT) and monoamine oxidase B (MAOB), and indirectly studied the activity of 5HT(2A) receptor (5HT(2A)r) in 15 hyperserotonemic (HS) and 17 normoserotonemic (NS) autistic subjects, and 15 healthy controls (C). While mean velocities of 5HTT kinetics did not significantly differ among the groups, significant elevation in the mean velocity of MAOB kinetics was observed in NS subjects and was even more pronounced in HS subjects in comparison to controls. Also, a decrease in adenosine 5'-diphosphate-induced platelet aggregation of borderline significance was observed in NS subjects, compared to C subjects. The results suggest a possibility of upregulation of monoaminergic synthesis/degradation and, probably consequential, downregulation of 5HT(2A)r in autistic subjects.
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PMID:Hyperserotonemia in autism: activity of 5HT-associated platelet proteins. 1922 90

The 5-HTTLPR polymorphism of serotonin transporter gene is widely investigated in association studies in autism spectrum disorders (ASD). The results of such studies, however, remain controversial possibly due to the great genetic heterogeneity related to ASD and the lack of evaluation of the triallelic functional structure of 5-HTTLPR. This study tested for association between the 5-HTTLPR and ASD in a Brazilian sample by case-control and family-based association test (FBAT) methods, considering the biallelic and triallelic structures of this polymorphism. In addition, we performed an exploratory analysis of associations between specific clinical outcomes of ASD patients and 5-HTTLPR as well as several prenatal environmental factors. Genotyping was achieved in 151 ASD patients, 179 unrelated controls and 105 complete trios. There was no evidence of association between the 5-HTTLPR with ASD in both case-control and FBAT tests, but the LaLa 5-HTTLPR genotype was associated with mood instability in patients (P=0.006). The prenatal exposure to potential neuroteratogenic drugs was associated with epilepsy (P<0.001). Our findings suggest that the 5-HTTLPR is not associated with ASD in the Brazilian population, even considering the triallelic structure. Additionally, this study suggested a role of the 5-HTTLPR and environmental factors in the clinical expression of ASD.
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PMID:Influence of the 5-HTTLPR polymorphism and environmental risk factors in a Brazilian sample of patients with autism spectrum disorders. 1928 2

The study of phenotypic variability in social impairments and comorbid emotional disorders in autism is important because it provides information on phenotypic differences that currently complicate diagnosis, research, and treatment of this disorder. Currently, though, relatively little is known about the processes that contribute to individual differences in social impairments and comorbidity in autism. In this paper, we present a model that suggests modifier processes (MPs), which are not necessarily specific to the syndrome refractor alter the expression of autism and contribute to fundamental behavioral and psychological differences in children diagnosed with this disorder. One MPs involves the somewhat surprising tendency of some children with higher functioning autism (HFA) to make attributions about other peoples thoughts, although they have social cognitive deficits Just as in other children, the attributions of children with HFA are linked to some of their behavioral problems Another MP involves the influence of differences in motivation associated with the behavioral activation and inhibition systems that can be assessed with measures of anterior EEG asymmetry. This dimension of motivation may be linked to how active but inappropriate and withdrawn children with HFA may appear. Third, differences in the self-monitoring of errors among children with HFA appear to be related to individual differences in IQ and social symptom severity in these children. The possible role of these MPs in diagnostic subgroups and differences in treatment responses among children with HFA are discussed. In addition, the role of MPs in understanding the effects associated with specific genetic functions in autism, such as those associated with the serotonin transporter gene (5-HTTLPR), is discussed. A conclusion of this paper is that the varied expression of autism may require that we understand how autism interacts with other non-syndrome-specific processes that are related to individual differences in all people.
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PMID:The Modifier Model of Autism and Social Development in Higher Functioning Children. 1989 85

We investigated whether the promoter region of the serotonin transporter gene (5-HTTLPR) polymorphism influenced neurochemical metabolism in 26 individuals with autism spectrum disorder. Individuals with the S/S genotype of the 5-HTTLPR polymorphism showed significantly lower levels of N-acetylaspartate/creatine in the right medial prefrontal cortex compared with those with the S/L genotype.
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PMID:5-HTTLPR polymorphism influences prefrontal neurochemical metabolites in autism spectrum disorder. 2061 17


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