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Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human serotonin transporter (hSERT) gene is a promising candidate for mediating the genetic susceptibility for various psychiatric conditions such as mood and obsessive-compulsive disorders. Two polymorphic sites in this gene attracted much interest: a VNTR of 17-bp repeats in intron two, and an insertion/deletion in the 5'-flanking promoter region (5-HTT gene-linked polymorphic region-5-HTTLPR) creating a short (S) and a long (L) allele. The 5-HTTLPR polymorphism is situated in a GC-rich region composed of 20-23 bp repeating units. The S and L alleles have 14 and 16 repeat-elements respectively. Positive associations of the 5-HTTLPR polymorphism with mood disorders, anxiety-related personality traits, autism and late-onset Alzheimer's disease have been published, although some non replications were also reported. Here we report a novel allele (termed LJ) in the 5-HTTLPR site. This allele is longer than the L allele by 43 bp, has 18 repeat units and contains two copies of the insertion/deletion sequence arranged in tandem. The LJ allele was found in individuals of Libyan and Tunisian Jewish origin but not in Moroccan or Ashkenazi Jews.
Mol Psychiatry 1999 Jan
PMID:A novel allele in the promoter region of the human serotonin transporter gene. 1008 18

Family and twin studies have suggested a genetic component in autism. We performed a genome-wide screen with 264 microsatellites markers in 51 multiplex families, using non-parametric linkage methods. Families were recruited by a collaborative group including clinicians from Sweden, France, Norway, the USA, Italy, Austria and Belgium. Using two-point and multipoint affected sib-pair analyses, 11 regions gave nominal P -values of 0.05 or lower. Four of these regions overlapped with regions on chromosomes 2q, 7q, 16p and 19p identified by the first genome-wide scan of autism performed by the International Molecular Genetic Study of Autism Consortium. Another of our potential susceptibility regions overlapped with the 15q11-q13 region identified in previous candidate gene studies. Our study revealed six additional regions on chromosomes 4q, 5p, 6q, 10q, 18q and Xp. We found that the most significant multipoint linkage was close to marker D6S283 (maximum lod score = 2.23, P = 0.0013).
Hum Mol Genet 1999 May
PMID:Genome-wide scan for autism susceptibility genes. Paris Autism Research International Sibpair Study. 1019 69

Recently, several studies have reported an association between anxiety traits, affective disorders and autism and alleles of a functional promoter polymorphism (5HTT-LPR) in the human serotonin transporter (5HTT, SERT).1-3 The mechanistic basis for allelic differences in transporter transcription are presently unknown. To explore this issue, we cloned the human 5HTT promoter region from a PAC genomic library and now describe an unreported 381-bp insert between the polymorphic region and the transcription start site. We verified the presence of this novel sequence by Southern hybridization of genomic digests and PCR amplifications from multiple unrelated individuals. Sequence analysis of the novel region reveals a number of canonical transcription factor binding sites (eg AP1, Elk1, NFkappaB) that may be important in controlling the response of the 5HTT gene to regulatory factors. PCR studies of genomic templates reveal a low level of amplification of a deleted template matching the size of the originally reported 5HTT promoter. This deleted template is absent from PAC amplifications, suggesting that the human 5HTT promoter may exhibit in vivo instability. Molecular Psychiatry (2000) 5, 110-115.
Mol Psychiatry 2000 Jan
PMID:Modified structure of the human serotonin transporter promoter. 1067 78

Family-based studies performed to date provide conflicting evidence of linkage/association between autistic disorder and either the "short" [Cook et al., 1997: Mol Psychiatry 2:247-250] or the "long" [Klauck et al., 1997: Hum Mol Genet 6:2233-2238] allele of a polymorphic repeat located in the serotonin transporter (5-HTT) gene promoter region, affecting 5-HTT gene expression [Lesch et al., 1996: Science 274:1527-1531]. The present study was designed to assess linkage and linkage disequilibrium in two new ethnically distinct samples of families with primary autistic probands. The 5-HTT promoter repeat was genotyped in 54 singleton families collected in Italy and in 32 singleton and 5 multiplex families collected in the U.S.A., yielding a total sample of 98 trios. Linkage/association between 5-HTT gene promoter alleles and autistic disorder was assessed using the transmission/disequilibrium test (TDT) and the haplotype-based haplotype relative risk (HHRR). Both the Italian and the American samples, either singly or combined, displayed no evidence of linkage/association between 5-HTT gene promoter alleles and autistic disorder. Our findings do not support prominent contributions of 5-HTT gene variants to the pathogenesis of idiopathic infantile autism. Heterogeneity in pathogenetic mechanisms underlying the disease may require that linkage/association studies be targeted toward patient subgroups isolated on the basis of specific biochemical markers, such as serotonin (5-HT) blood levels. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:123-127, 2000.
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PMID:Lack of association between serotonin transporter gene promoter variants and autistic disorder in two ethnically distinct samples. 1068 65

The serotonin receptor 2B gene (HTR2B; MIM 601122) is a pharmacological and positional candidate gene in early-onset obsessive-compulsive disorder. Sequences of a putative promoter region and splice regions were first elucidated, then sequenced along with HTR2B coding regions. Probands from seven families included in a previous genome scan in which one of the strongest linkage findings was to a region including HTR2B, along with two genomic DNA pools of 10 unrelated control subjects and 10 unrelated autism probands were screened. One single nucleotide polymorphism was found in intron 1, that may be useful as a marker in genetic linkage and association studies. It does not appear likely to affect splicing. No evidence for functional mutation was found in the sequenced regions of HTR2B.
Mol Cell Probes 2000 Feb
PMID:Mutation screening of human 5-HT(2B)receptor gene in early-onset obsessive-compulsive disorder. 1072 92

Autism (MIM 209850) is a severe neuropsychiatric disorder of unknown aetiology with profound consequences for patients and their families. Strong evidence from twin and family studies indicates the importance of genetic factors in the development of idiopathic autism, although it is clear that these influences are complex. This review focuses on recent molecular investigations to identify susceptibility loci implicated in autistic disorder.
Hum Mol Genet 2000 Apr 12
PMID:Autism: recent molecular genetic advances. 1076 8

The reputation of the field of psychiatric genetics has recently become tarnished in the view of many human geneticists. Too many linked loci were claimed and withdrawn, too many association studies published and not confirmed and, more recently, too many new and different chromosomal regions have been implicated for the same disorder. Here, we summarize recent trends, focusing on research that moves away from traditional linkage studies. Some promising strategies include psychopharmacogenetics, and consideration of endophenotypes such as neurophysiological and behavioral markers in addition to the clinical diagnosis. Utilization of rapid and automated methods for scoring genetic variants in large-scale association studies followed by multivariate analyses, which include environmental as well as genetic data, will likely fare better than traditional linkage analysis in disentangling the complex genetics of psychiatric disorders. Some notable areas of recent progress include quantification of the genetic complexity of autism, identification of genetic variants protecting individuals from alcoholism, and the description of several polymorphisms likely to be relevant to behavior and psychiatry. The most notable example may be a common variant that affects the transcription rate in the promoter for the serotonin transporter gene that may be relevant for individual differences in the response to common anti-depressants.
Hum Mol Genet 2000 Apr 12
PMID:Recent progress in psychiatric genetics-some hope but no hype. 1076 16

Autism, the prototypical pervasive developmental disorder, is characterized by impaired communication and social interaction, and by repetitive interests and behaviours. The core disorder probably affects around 5:10 000 individuals, of whom some three-quarters are male. Onset is in the first three years of life, and the disorder is associated with lifelong disabilities. Because of the clear evidence that idiopathic autism has a strong genetic basis, many groups are undertaking whole genome screens to identify susceptibility loci. We review the first results, and briefly consider the implications of molecular genetic findings for future research, diagnosis and management.
Mol Med Today 2000 Jun
PMID:Genetic clues to the biological basis of autism. 1084 Mar 82

NESP55, a novel member of the chromogranins, was originally implicated as a precursor of a peptide LSAL with 5-HT1B receptor antagonist activity. In humans, NESP55 (MIM 139320) is encoded by an alternative transcript of GNAS1, the gene encoding the guanine nucleotide-binding alpha subunit of G(S). As a result of the potential relevance of NESP55 to serotoninergic neurotransmission, we screened its sequence using genomic DNA pools from autistic disorder, obsessive-compulsive disorder (OCD) probands and control subjects. Six single nucleotide polymorphisms (SNPs) were identified and the allele frequencies of those SNPs were determined. In addition, a 24-bp in-frame deletion in the coding region was found in one of the OCD probands. To further investigate its pattern of inheritance and the relevance to studied phenotypes, we genotyped 123 total subjects from autism, OCD and attention deficit hyperactivity disorder (ADHD) families. The deletion was detected only in one OCD family and followed Mendelian inheritance. All subjects with the deletion were heterozygous. However, there are no specific behavioural or physical alterations in the subjects with this deletion variant. The physiological role of NESP55 in serotoninergic neurotransmission as well as the effect of the deletion on its function should be evaluated in future studies.
Mol Cell Probes 2000 Jun
PMID:Deletion polymorphism in the coding region of the human NESP55 alternative transcript of GNAS1. 1086 Jul 17

The role of genetic factors in the etiology of the autistic spectrum of disorders has clearly been demonstrated. Ten chromosomal regions, on chromosomes 1p, 4p, 6q, 7q, 13q, 15q, 16p, 17q, 19q and 22q have potentially been linked to autism.1-8 We have analyzed these chromosomal regions in a total of 17 multiplex families with autism originating from the isolated Finnish population by pairwise linkage analysis and sib-pair analysis. Mild evidence for putative contribution was found only with the 1p chromosomal region in the susceptibility to autism. Our data suggest that additional gene loci exist for autism which will be detectable in and even restricted to the isolated Finnish population.
Mol Psychiatry 2000 May
PMID:Analysis of autism susceptibility gene loci on chromosomes 1p, 4p, 6q, 7q, 13q, 15q, 16p, 17q, 19q and 22q in Finnish multiplex families. 1088 36


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