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)

Sodium-coupled transporters are ubiquitous pumps that harness pre-existing sodium gradients to catalyse the thermodynamically unfavourable uptake of essential nutrients, neurotransmitters and inorganic ions across the lipid bilayer. Dysfunction of these integral membrane proteins has been implicated in glucose/galactose malabsorption, congenital hypothyroidism, Bartter's syndrome, epilepsy, depression, autism and obsessive-compulsive disorder. Sodium-coupled transporters are blocked by a number of therapeutically important compounds, including diuretics, anticonvulsants and antidepressants, many of which have also become indispensable tools in biochemical experiments designed to probe antagonist binding sites and to elucidate transport mechanisms. Steady-state kinetic data have revealed that both competitive and noncompetitive modes of inhibition exist. Antagonist dissociation experiments on the serotonin transporter (SERT) have also unveiled the existence of a low-affinity allosteric site that slows the dissociation of inhibitors from a separate high-affinity site. Despite these strides, atomic-level insights into inhibitor action have remained elusive. Here we screen a panel of molecules for their ability to inhibit LeuT, a prokaryotic homologue of mammalian neurotransmitter sodium symporters, and show that the tricyclic antidepressant (TCA) clomipramine noncompetitively inhibits substrate uptake. Cocrystal structures show that clomipramine, along with two other TCAs, binds in an extracellular-facing vestibule about 11 A above the substrate and two sodium ions, apparently stabilizing the extracellular gate in a closed conformation. Off-rate assays establish that clomipramine reduces the rate at which leucine dissociates from LeuT and reinforce our contention that this TCA inhibits LeuT by slowing substrate release. Our results represent a molecular view into noncompetitive inhibition of a sodium-coupled transporter and define principles for the rational design of new inhibitors.
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PMID:Antidepressant binding site in a bacterial homologue of neurotransmitter transporters. 1768 33

Complex human diseases do not have a clear inheritance pattern, and it is expected that risk involves multiple genes with modest effects acting independently or interacting. Major challenges for the identification of genetic effects are genetic heterogeneity and difficulty in analyzing high-order interactions. To address these challenges, we present MDR-Phenomics, a novel approach based on the multifactor dimensionality reduction (MDR) method, to detect genetic effects in pedigree data by integration of phenotypic covariates (PCs) that may reflect genetic heterogeneity. The P value of the test is calculated using a permutation test adjusted for multiple tests. To validate MDR-Phenomics, we compared it with two MDR-based methods: (1) traditional MDR pedigree disequilibrium test (PDT) without consideration of PCs (MDR-PDT) and (2) stratified phenotype (SP) analysis based on PCs, with use of MDR-PDT with a Bonferroni adjustment (SP-MDR). Using computer simulations, we examined the statistical power and type I error of the different approaches under several genetic models and sampling scenarios. We conclude that MDR-Phenomics is more powerful than MDR-PDT and SP-MDR when there is genetic heterogeneity, and the statistical power is affected by sample size and the number of PC levels. We further compared MDR-Phenomics with conditional logistic regression (CLR) for testing interactions across single or multiple loci with consideration of PC. The results show that CLR with PC has only slightly smaller power than does MDR-Phenomics for single-locus analysis but has considerably smaller power for multiple loci. Finally, by applying MDR-Phenomics to autism, a complex disease in which multiple genes are believed to confer risk, we attempted to identify multiple gene effects in two candidate genes of interest--the serotonin transporter gene (SLC6A4) and the integrin beta 3 gene (ITGB3) on chromosome 17. Analyzing four markers in SLC6A4 and four markers in ITGB3 in 117 white family triads with autism and using sex of the proband as a PC, we found significant interaction between two markers--rs1042173 in SLC6A4 and rs3809865 in ITGB3.
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PMID:Multifactor dimensionality reduction-phenomics: a novel method to capture genetic heterogeneity with use of phenotypic variables. 1799 63

The serotonin transporter promoter length polymorphism (5-hydroxytryptamine transporter length polymorphism, 5-HTTLPR) in serotonin transporter gene has been implicated in numerous psychiatric disorders. Having a high affinity for the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT), serotonin transporter controls the duration, availability and signaling capacity of 5-HT in the synapse. Association studies have focused extensively on this polymorphic region as the frequencies of long- and short-alleles of this gene differ greatly amongst populations and association studies have either reported conflicting results or nothing significant at all. In this study, the genotype and allele frequencies of 5-HTTLPR polymorphism were determined in the healthy South African (SA) individuals belonging to diverse ethnic backgrounds. Cheek cell samples were collected from the three major ethnic groups namely: Caucasians, Africans and coloreds/Mixed population. The DNA was extracted and genotyped for the 5-HTTLPR. Genotypes were compared amongst the three major ethnic groups from SA as well as to that of other studies around the world. This is the first study to report significant differences in the 5-HTTLPR genotype and allelic frequencies among various ethnic groups in SA. Future studies will target larger population groups and the estimation of frequency of these alleles in individuals with autism.
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PMID:The 5-HTTLPR polymorphism in South African healthy populations: a global comparison. 1819 79

The serotonin transporter gene (5-HTT) plays a crucial role in serotonergic neurotransmission and has been found to be associated, with varying degrees of significance, with many diseases, including autism. Prior association studies of autism have yielded conflicting results regarding the association between two common 5-HTT polymorphisms, the promoter insertion/deletion (5-HTTLPR) and the intron 2 VNTR (STin2 VNTR). We conducted a systematic review and meta-analysis to test the following hypotheses: (i) there is an association between autism and either or both of the 5-HTTLPR and STin2 VNTR polymorphisms, and (ii) the S allele of 5-HTTLPR and/or the STin2.12 allele of the VNTR are the specific risk alleles for autism. All published family-based and population based studies were examined to determine the overall strength of association between 5-HTT polymorphisms and autism. After exclusion of studies with overlapping samples and studies whose data did not allow for calculation of an odds ratio, 16 studies were included for final analyses, all but two of which used a family-based design. The meta-analysis failed to find a significant overall association between either of the 5-HTT polymorphisms examined and autism. Further, no allelic transmission distortion was found when studies of simplex (11 studies) and multiplex (3 studies) family samples were analyzed separately. However, there was significant heterogeneity by ethnicity; family based studies of US mixed population samples showed preferential transmission of the S allele of 5-HTTLPR (S allele:L allele = 247:183), while there was no allelic distortion among the family-based studies of European and Asian samples.
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PMID:Autism and serotonin transporter gene polymorphisms: a systematic review and meta-analysis. 1828 33

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

Disturbances in the serotonergic system have been recognized in autism. To investigate the association between serotonin and dopamine transporters and autism, we studied 15 children (14 males, one female; mean age 8 y 8 mo [SD 3 y 10 mo]) with autism and 10 non-autistic comparison children (five males, five females; mean age 9 y 10 mo [SD 2 y 8 mo]) using single-photon emission computed tomography (SPECT) with [123 I] nor-beta-CIT. The children, with autism were studied during light sedation. They showed reduced serotonin transporter (SERT) binding capacity in the medial frontal cortex, midbrain, and temporal lobe areas. However, after correction due to the estimated effect of sedation, the difference remained significant only in the medial frontal cortex area (p=0.002). In the individuals with autism dopamine transporter (DAT) binding did not differ from that of the comparison group. The results indicate that SERT binding capacity is disturbed in autism. The reduction is more evident in adolescence than in earlier childhood. The low SERT binding reported here and the low serotonin synthesis capacity shown elsewhere may indicate maturation of a lesser number of serotonergic nerve terminals in individuals with autism.
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PMID:Serotonin and dopamine transporter binding in children with autism determined by SPECT. 1875 90

Profound impairment in social interaction is a core symptom of autism, a severe neurodevelopmental disorder. Deficits can include a lack of interest in social contact and low levels of approach and proximity to other children. In this study, a three-chambered choice task was used to evaluate sociability and social novelty preference in five lines of mice with mutations in genes implicated in autism spectrum disorders. Fmr1(tm1Cgr/Y)(Fmr1(-/y)) mice represent a model for fragile X, a mental retardation syndrome that is partially comorbid with autism. We tested Fmr1(-/y)mice on two genetic backgrounds, C57BL/6J and FVB/N-129/OlaHsd (FVB/129). Targeted disruption of Fmr1 resulted in low sociability on one measure, but only when the mutation was expressed on FVB/129. Autism has been associated with altered serotonin levels and polymorphisms in SLC6A4 (SERT), the serotonin transporter gene. Male mice with targeted disruption of Slc6a4 displayed significantly less sociability than wild-type controls. Mice with conditional overexpression of Igf-1 (insulin-like growth factor-1) offered a model for brain overgrowth associated with autism. Igf-1 transgenic mice engaged in levels of social approach similar to wild-type controls. Targeted disruption in other genes of interest, En2 (engrailed-2) and Dhcr7, was carried on genetic backgrounds that showed low levels of exploration in the choice task, precluding meaningful interpretations of social behavior scores. Overall, results show that loss of Fmr1 or Slc6a4 gene function can lead to deficits in sociability. Findings from the fragile X model suggest that the FVB/129 background confers enhanced susceptibility to consequences of Fmr1 mutation on social approach.
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PMID:Social approach in genetically engineered mouse lines relevant to autism. 1901 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

There is increasing evidence that people with autism spectrum disorders (ASDs) have abnormalities in the serotonergic system. For example, a functional polymorphism of the serotonin transporter gene promoter region (5HTTLPR long/short polymorphism) has been reported to confer risk for ASDs, and to affect cortical grey matter volume in young children. However, the persistence of this association later in development is unknown. Hence, we investigated whether variation in the 5HTTLPR long/short polymorphism modulates brain anatomy in older people with ASD. We related 5HTTLPR long/short polymorphism in 43 adolescents and adults with ASD to brain anatomy using structural magnetic resonance imaging and voxel-based morphometry. There were no significant associations between brain anatomy and genotype. When considered alongside evidence of a relationship between 5HTTLPR genotype and brain volume amongst children with autism, our findings raise the possibility that the relationship between 5HTTLPR polymorphism and brain anatomy in ASDs anatomy may differ as a function of age and/or ASD subdiagnosis.
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PMID:Serotonin transporter genotype and neuroanatomy in autism spectrum disorders. 1936 12

The serotonin transporter knockout (SERT(-/-)) mouse, generated in 1998, was followed by the SERT(-/-) rat, developed in 2006. The availability of SERT(-/-) rodents creates the unique possibility to study the conservation of gene function across species. Here we summarize SERT(-/-) mouse and rat data, and discuss species (dis)similarities in neurobehavioral endophenotypes. Both SERT(-/-) rodent models show a disturbed serotonergic system, altered nociception, higher anxiety, decreased social behavior, as well as increased negative emotionality, behavioral inhibition and decision making. Used to model a wide range of psychiatric disorders, SERT(-/-) rodents may be particularly valuable in research on neurodevelopmental disorders such as depression, anxiety, and possibly autism. We conclude that SERT function is conserved across mice and rats and that their behavioral profile arises from common neurodevelopmental alterations. Because mice and rats have species-specific characteristics that confer differential research advantages, a comparison of the two models has heuristic value in understanding the mechanisms and behavioral outcome of SERT genetic variation in humans.
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PMID:Conserved role for the serotonin transporter gene in rat and mouse neurobehavioral endophenotypes. 1969 44


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