Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Based on recent studies of neuroimmune networks, the lymphocyte binding of serotonin neurotransmitter was studied in patients with Alzheimer's disease, idiopathic mental retardation, and autism. The specific binding to lymphocytes of [3H]serotonin, at a single concentration of 100 nM, was significantly reduced in Alzheimer's disease patients as compared to aged controls (group mean of 3.667 +/- 2.301 v 7.506 +/- 1.717 picomoles; p = 0.001), and in children with idiopathic mental retardation as compared to healthy children (group mean of 3.694 +/- 1.627 v 5.792 +/- 1.902 picomoles; p = 0.003). However, autistic children did not differ significantly from the healthy children (group mean of 5.287 +/- 1.987 v 5.792 +/- 1.902 picomoles; p = 0.475). Reduced lymphocyte binding of serotonin may be an indication of breakdown of an unknown neuroimmune pathway relevant to the pathophysiology of Alzheimer's disease and idiopathic mental retardation.
Mol Chem Neuropathol 1990 Dec
PMID:Binding of [3H]serotonin to lymphocytes in patients with neuropsychiatric disorders. 209 81

We have previously identified two genes (EMS1 and PRAD1/cyclin D1) in the chromosome 11q13 region that are frequently coamplified and overexpressed in human breast cancer and in squamous cell carcinomas of the head and neck (E. Schuuring, E. Verhoeven, W.J. Mooi, and R.J.A.M. Michalides, Oncogene 7:355-361, 1992). We now report on the characterization of the 80/85-kDa protein that is encoded by the EMS1 gene. Amino acid sequence comparison shows a high homology (85%) to a chicken protein that was recently identified as a substrate for the src oncogene (H. Wu, A.B. Reynolds, S.B. Kanner, R.R. Vines, and J.T. Parsons, Mol. Cell. Biol. 11:5113-5124, 1991). Immunocytochemistry reveals that in epithelial cells, the human EMS1 protein is localized mainly in the cytoplasm and, to a very low extent, in protruding leading lamellae of the cell. However, in carcinoma cells that constitutively overexpress the protein as a result of amplification of the EMS1 gene, the protein, except in cytoplasm, accumulates in the podosome-like adherens junctions associated with the cell-substratum contact sites. The protein was not found in intercellular adherens junctions. Our findings, and the previously reported observations in src-transformed chicken embryo fibroblasts, suggest that the EMS1 protein is involved in regulating the interactions between components of adherens-type junctions. Since amplification of the 11q13 region has been associated with an enhanced invasive potential of these tumors, overexpression and concomitant accumulation of the EMS1 protein in the cell-substratum contact sites might, therefore, contribute to the invasive potential of these tumor cells.
Mol Cell Biol 1993 May
PMID:The product of the EMS1 gene, amplified and overexpressed in human carcinomas, is homologous to a v-src substrate and is located in cell-substratum contact sites. 847 48

The two most consistent features of the diseases caused by trinucleotide repeat expansion-neuropsychiatric symptoms and the phenomenon of genetic anticipation-may be present in forms of dementia, hereditary ataxia, Parkinsonism, bipolar affective disorder, schizophrenia and autism. To identify candidate genes for these disorders, we have screened human brain cDNA libraries for the presence of gene fragments containing polymorphic trinucleotide repeats. Here we report the cDNA cloning of CAGR1, originally detected in a retinal cDNA library. The 2743 bp cDNA contains a 1077 bp open reading frame encoding 359 amino acids. This amino acid sequence is homologous (56% amino acid identify and 81% amino acid conservation) to the Caenorhabditis elegans cell fate-determining protein mab-21. CAGR1 is expressed in several human tissues, most prominently in the cerebellum, as a message of approximately 3.0 kb. The gene was mapped to 13q13, just telomeric to D13S220. A 5'-untranslated CAG trinucleotide repeat is highly polymorphic, with repeat length ranging from six to 31 triplets and a heterozygosity of 87-88% in 684 chromosomes from several human populations. One allele from an individual with an atypical movement disorder and bipolar affective disorder type II contains 46 triplets, 15 triplets longer than any other allele detected. Though insufficient data are available to link the long repeat to this clinical phenotype, an expansion mutation of the CAGR1 repeat can be considered a candidate for the etiology of disorders with anticipation or developmental abnormalities, and particularly any such disorders linked to chromosome 13.
Hum Mol Genet 1996 May
PMID:cDNA cloning of a human homologue of the Caenorhabditis elegans cell fate-determining gene mab-21: expression, chromosomal localization and analysis of a highly polymorphic (CAG)n trinucleotide repeat. 873 27

The major histocompatibility complex comprises a number of genes that control the function and regulation of the immune system. One of these genes, the C4B gene, encodes a product that is involved in eliminating pathogens such as viruses and bacteria from the body. We previously reported that a deficient form of the C4B gene, termed the C4B null allele (no C4B protein produced) had an increased frequently in autism. In this study we attempted to confirm the increased incidence of the C4B null allele in autism and investigated the presence of a C4B null allele in two other childhood disorders, attention-deficit hyperactivity disorder and dyslexia (reading disability). In addition, we explored the relationship of autism to the DR beta 1 gene, a gene located close to the C4B in autism. We confirmed the finding of an increased frequency of the C4B null allele in autism and found that the related disorders also had an increased frequency of this null allele. In addition, two alleles of the DR beta 1 gene also had significantly increased representation in the autistic subjects.
Mol Chem Neuropathol
PMID:Immunogenetic studies in autism and related disorders. 887 44

We have analysed all 17 exons of the human FMR-1 gene for mutations in autistic individuals using single-stranded conformational polymorphism (SSCP) analysis. We have identified three new polymorphisms. SSCP DNA fragment shifts were found for exons, 5, 10 and 11 in autistic individuals and in normal controls. Sequence analysis showed the exon 10 and 11 polymorphisms to result from base substitutions within introns, 14 and 73 bp downstream from the splice site respectively. In exon 5, a G to A base substitution at codon 138 has no effect on amino acid sequence. The intronic polymorphism adjacent to exon 10 was analysed amongst two groups of unrelated autistic individuals-one from the UK and one from Germany- and amongst a control population. Comparison of allele frequencies between Caucasian autism cases and Caucasian controls show a significant increase in the presence of the polymorphic intronic sequence 3' to exon 10 (Fisher's exact test, P = 0.01). The base change is at a position where it is unlikely to affect splicing of the FMR-1 transcript and is most likely a neutral variant that has only a spurious false positive association with autism. However further linkage disequilibrium analyses are justifiable. The positive association with autism should be explored in further samples to determine whether it has any validity as a genetic marker for autism.
Mol Psychiatry 1996 Jul
PMID:Point mutation analysis of the FMR-1 gene in autism. 911 47

An X;8 translocation was identified in a 27-year-old female patient manifesting multiple exostoses and autism accompanied by mental retardation and epilepsy. Through molecular analysis using yeast artificial chromosomes (YACs) and cosmid clones, the translocation breakpoint was isolated and confirmed to be reciprocal within a 5'-GGCA-3' sequence found on both X and 8 chromosomes without gain or loss of a single nucleotide. The translocation breakpoint on the X chromosome occurred in the first intron of the gastrin-releasing peptide receptor (GRPR) gene and that on chromosome 8 occurred approximately 30 kb distal to the 3' end of the Syndecan-2 gene (SDC2), also known as human heparan sulfate proteoglycan or fibroglycan. The GRPR gene was shown to escape X-inactivation. A dosage effect of the GRPR and a position effect of the SDC2 gene may, however, contribute the phenotype observed in this patient since the orientation of these genes with respect to the translocation was incompatible with the formation of a fusion gene. Investigation of mutations in these two genes in unrelated patients with either autism or multiple exostoses as well as linkage and association studies is needed to validate them as candidate genes.
Hum Mol Genet 1997 Aug
PMID:Autism and multiple exostoses associated with an X;8 translocation occurring within the GRPR gene and 3' to the SDC2 gene. 925 69

An association study was performed to elucidate the role of the serotonin transporter (5-HTT) gene as a susceptibility factor for autism as treatment of patients with antidepressant drugs which selectively target 5-HTT reduced autistic or concomitant symptoms, such as repetitive behavior and aggression, and ameliorate language use. Using the transmission/disequilibrium test (TDT) an analysis was done for a common polymorphism in the upstream regulatory region (5-HTTLPR), a VNTR in intron 2 of the gene and a haplotype of both loci in 52 trios fulfilling stringent criteria for autism and an extended group of 65 trios including patients showing no language delay in their first 3 years of life. A higher frequency and preferential transmission of the long allele of the 5-HTTLPR was observed, but the TDT gave a statistically significant value ( P = 0. 032) only for the extended patient group. This result is in contrast to a recent study by a US group presenting preliminary evidence for preferential transmission of the short allele of 5-HTTLPR in 86 trios. Both studies failed to reveal significant linkage disequilibrium between the VNTR in intron 2 of the gene and autism. In our study haplotype analysis of the 5-HTTLPR and the VNTR in intron 2 supplied evidence for an association of 5-HTT and autism in the stringent ( P = 0.069) and extended patient group ( P = 0.049). Overall, we were not able to replicate the findings of the first study on 5-HTT and autism and instead observed a tendency for association of the opposite genetic variant of the gene with the disorder. The implications for genetic variants of the serotonin transporter in the etiology of autism and possible subgroups of patients, therefore, needs clarification in further studies with other and larger patient samples.
Hum Mol Genet 1997 Dec
PMID:Serotonin transporter (5-HTT) gene variants associated with autism? 936 Oct 27

Autism is characterized by impairments in reciprocal social interaction and communication, and restricted and sterotyped patterns of interests and activities. Developmental difficulties are apparent before 3 years of age and there is evidence for strong genetic influences most likely involving more than one susceptibility gene. A two-stage genome search for susceptibility loci in autism was performed on 87 affected sib pairs plus 12 non-sib affected relative-pairs, from a total of 99 families identified by an international consortium. Regions on six chromosomes (4, 7, 10, 16, 19 and 22) were identified which generated a multipoint maximum lod score (MLS) > 1. A region on chromosome 7q was the most significant with an MLS of 3.55 near markers D7S530 and D7S684 in the subset of 56 UK affected sib-pair families, and an MLS of 2.53 in all 87 affected sib-pair families. An area on chromosome 16p near the telomere was the next most significant, with an MLS of 1.97 in the UK families, and 1.51 in all families. These results are an important step towards identifying genes predisposing to autism; establishing their general applicability requires further study.
Hum Mol Genet 1998 Mar
PMID:A full genome screen for autism with evidence for linkage to a region on chromosome 7q. International Molecular Genetic Study of Autism Consortium. 954 21

Obsessive compulsive disorder (OCD) is characterized by recurrent and intrusive thoughts that are distressing (obsessions) and/or repetitive behaviors or mental acts that the person feels driven to perform (compulsions). OCD has a partly genetic basis. For treatment of OCD, potent serotonin reuptake inhibitor (SRI) drugs (clomipramine (Anafranil), fluvoxamine (Luvox), fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil)), which act on the serotonin transporter protein, are uniquely efficacious. A polymorphism in the promoter region of the gene (SLC6A4) encoding this protein, was recently reported to affect protein expression and to be associated with measures of anxiety and depression and with autism (using a family-controlled transmission disequilibrium test (TDT) design). SLC6A4 therefore has strong a priori support for potentially influencing risk for OCD: the protein it encodes is a medication target; a polymorphism in the gene affects function; and that polymorphism has been shown to be associated with behavioral phenotypes. We used the TDT with a set of 34 European-American family trios, 30 unrelated and four drawn from an extended pedigree, to test for linkage disequilibrium between OCD and alleles at the SLC6A4 promoter polymorphic locus. Of 35 heterozygous parents, 24 transmitted the 'l' SLC6A4 allele and 11 transmitted the 's' allele (chi 2 TDT = 4.83; P < 0.03). Considering only the 13 SRI drug nonresponders, there were 13 heterozygous parents, of whom 10 transmitted the 'l' allele and three the 's' allele (chi 2 TDT = 3.77; P < 0.052). These data provide preliminary support for association and linkage disequilibrium between the SLC6A4 'l' allele and OCD.
Mol Psychiatry 1998 May
PMID:Evidence for linkage disequilibrium between serotonin transporter protein gene (SLC6A4) and obsessive compulsive disorder. 967 4

Previous reports of individuals with autistic disorder with maternal duplications of 15q11-q13, the Prader-Willi/Angelman syndrome region, suggest this area as a source of candidate genes in autistic disorder. Maternal truncation mutations in UBE3A, which encodes for E6-AP ubiquitin-protein ligase, have been shown to cause Angelman syndrome, which can also result from the absence of maternal chromosomal material from this region. Despite showing no evidence for imprinting in other tissues, this gene was recently discovered to be preferentially maternally expressed in human brain and expressed solely from the murine maternal chromosome in the hippocampus and cerebellar Purkinje cells, regions implicated in the neuropathology of autism. Based on this evidence, the coding region and a putative promoter region were sequenced in ten autistic subjects. Several polymorphisms were detected, but no evidence was found for a functional mutation. Evidence for likely altered regulation of UBE3A expression in maternal 15q11-q13 duplications suggests further investigation of the regulatory regions of this gene in autistic disorder.
Mol Psychiatry 1999 Jan
PMID:Mutation screening of the UBE3A/E6-AP gene in autistic disorder. 1008 11


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