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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We applied genetic tools available in Drosophila to identify candidate substrates of the UBE3A ubiquitin ligase, the gene responsible for Angelman syndrome (AS). Human UBE3A was expressed in Drosophila heads to identify proteins differentially regulated in UBE3A-expressing versus wild-type extracts. Using two-dimensional gel and MALDI-TOF analysis, we detected 20 proteins that were differentially regulated by over-expression of human UBE3A in Drosophila heads. One protein responsive to UBE3A was the Rho-GEF pebble (pbl). Here, we present three lines of evidence suggesting that UBE3A regulates Pbl. First, we show genetic evidence that UBE3A and the Drosophila de-ubiquitinase fat facets (faf) exert opposing effects on Pbl function. Secondly, we find that both Pbl and ECT2, the mammalian orthologue of Pbl called epithelial cell transforming sequence 2 oncogene, physically interact with their respective ubiquitin E3 ligases. Finally, we show that Ect2 expression is regulated by Ube3a in mouse neurons as the pattern of Ect2 expression is dramatically altered in the hippocampus and cerebellum of Ube3a null mice. These results suggest that an orthologous UBE3A post-translational regulatory pathway regulates neuronal outgrowth in the mammalian brain and that dysregulation of this pathway may result in neurological phenotypes including AS and possibly other autism spectrum disorders.
Hum Mol Genet 2006 Sep 15
PMID:Expression of the Rho-GEF Pbl/ECT2 is regulated by the UBE3A E3 ubiquitin ligase. 1690 59

An episode of hyperthermia is not uncommon during pregnancy. The consequences depend on the extent of temperature elevation, its duration, and the stage of development when it occurs. Mild exposures during the preimplantation period and more severe exposures during embryonic and fetal development often result in prenatal death and abortion. Hyperthermia also causes a wide range of structural and functional defects. The central nervous system (CNS) is most at risk probably because it cannot compensate for the loss of prospective neurons by additional divisions by the surviving neuroblasts and it remains at risk at stages throughout pre- and postnatal life. In experimental animals the most common defects are of the neural tube, microphthalmia, cataract, and micrencephaly, with associated functional and behavioral problems. Defects of craniofacial development including clefts, the axial and appendicular skeleton, the body wall, teeth, and heart are also commonly found. Nearly all these defects have been found in human epidemiological studies following maternal fever or hyperthermia during pregnancy. Suggested future human studies include problems of CNS function after exposure to influenza and fever, including mental retardation, schizophrenia, autism, and cerebral palsy.
Birth Defects Res A Clin Mol Teratol 2006 Jul
PMID:Review: Hyperthermia and fever during pregnancy. 1693 4

Autism has a strong genetic background with a higher frequency of affected males suggesting involvement of X-linked genes and possibly also other factors causing the unbalanced sex ratio in the etiology of the disorder. We have identified two missense mutations in the ribosomal protein gene RPL10 located in Xq28 in two independent families with autism. We have obtained evidence that the amino-acid substitutions L206M and H213Q at the C-terminal end of RPL10 confer hypomorphism with respect to the regulation of the translation process while keeping the basic translation functions intact. This suggests the contribution of a novel, possibly modulating aberrant cellular function operative in autism. Previously, we detected high expression of RPL10 by RNA in situ hybridization in mouse hippocampus, a constituent of the brain limbic system known to be afflicted in autism. Based on these findings, we present a model for autistic disorder where a change in translational function is suggested to impact on those cognitive functions that are mediated through the limbic system.
Mol Psychiatry 2006 Dec
PMID:Mutations in the ribosomal protein gene RPL10 suggest a novel modulating disease mechanism for autism. 1694 Sep 77

The autism spectrum disorders (ASD) comprise a complex group of behaviorally related disorders that are primarily genetic in origin. Involvement of epigenetic regulatory mechanisms in the pathogenesis of ASD has been suggested by the occurrence of ASD in patients with disorders arising from epigenetic mutations (fragile X syndrome) or that involve key epigenetic regulatory factors (Rett syndrome). Moreover, the most common recurrent cytogenetic abnormalities in ASD involve maternally derived duplications of the imprinted domain on chromosome 15q11-13. Thus, parent of origin effects on sharing and linkage to imprinted regions on chromosomes 15q and 7q suggest that these regions warrant specific examination from an epigenetic perspective, particularly because epigenetic modifications do not change the primary genomic sequence, allowing risk epialleles to evade detection using standard screening strategies. This review examines the potential role of epigenetic factors in the etiology of ASD.
Hum Mol Genet 2006 Oct 15
PMID:Epigenetics of autism spectrum disorders. 1698 77

Secretin is a peptide hormone released from the duodenum to stimulate the secretion of digestive juice by the pancreas. Secretin also functions as a neuropeptide hormone in the brain, and exogenous administration has been reported to alleviate symptoms in some patients with autism. We have generated secretin receptor-deficient mice to explore the relationship between secretin signaling in the brain and behavioral phenotypes. Secretin receptor-deficient mice are overtly normal and fertile; however, synaptic plasticity in the hippocampus is impaired and there are slightly fewer dendritic spines in the CA1 hippocampal pyramidal cells. Furthermore, secretin receptor-deficient mice show abnormal social and cognitive behaviors. These findings suggest that the secretin receptor system has an important role in the central nervous system relating to social behavior.
Hum Mol Genet 2006 Nov 01
PMID:Secretin receptor-deficient mice exhibit impaired synaptic plasticity and social behavior. 1700 57

Twin and family studies in autistic disorders (AD) have elucidated a high heritability of the narrow and broad phenotype of AD. In this review on the genetics of AD, we will initially delineate the phenotype of AD and discuss aspects of differential diagnosis, which are particularly relevant with regard to the genetics of autism. Cytogenetic and molecular genetic studies will be presented in detail, and the possibly involved aetiopathological pathways will be described. Implications of the different genetic findings for genetic counselling will be mentioned.
Mol Psychiatry 2007 Jan
PMID:The genetics of autistic disorders and its clinical relevance: a review of the literature. 1703 36

One-third of women with Turner syndrome (45,X) have autism-like social and communication difficulties, despite normal verbal IQ. Deletion mapping of the X-chromosome implicated 5 Mb of Xp11.3-4 as critical for recognition of facial fear, a quantitative measure of social cognition. Variability in fear recognition accuracy in Turner syndrome suggested the existence of a quantitative trait locus (QTL) revealed by X-monosomy. We aimed to identify the gene(s) influencing fear recognition by dense mapping of the 5 Mb region. Initial regression-based association mapping of fear recognition in 93 women with Turner syndrome across the critical region was performed, using genotype data at 242 single nucleotide polymorphisms (SNPs). We identified three regions of interest, in which 52 additional SNPs were genotyped. The third region then contained four SNPs associated with fear recognition (0.0030 > P > 0.00046). We obtained an independent sample of 77 Turner syndrome females that we genotyped for 77 SNPs in the initial regions of interest. Region three showed association in the same direction, maximal at SNPs rs7055196 and rs7887763 (P = 0.022 each). Four SNPs in strong linkage disequilibrium (LD), including this pair, span 40 kb within a novel transcript, EF-hand domain containing 2 (EFHC2). In the combined Turner syndrome samples, the most strongly associated SNP (P = 0.00007) has frequency of 8.8% and an estimated effect size accounting for over 13% of the variance in fear recognition. EFHC2 shows genealogy and extended LD consistent with directional selection. This novel QTL may influence social cognition in the general population and in autism.
Hum Mol Genet 2007 Jan 01
PMID:Identification of EFHC2 as a quantitative trait locus for fear recognition in Turner syndrome. 1716 67

Autism is a common neurodevelopmental disorder with a significant genetic component and locus heterogeneity. To date, 12 microsatellite genome screens have been performed using various data sets of sib-pair families (parents and affected children) resulting in numerous regions of potential linkage across the genome. However, no universal region or consistent candidate gene from these regions has emerged. The use of large, extended pedigrees is a recognized powerful approach to identify significant linkage results, as these families potentially contain more potential linkage information than sib-pair families. A genome-wide linkage analysis was performed on 26 extended autism families (65 affected, 184 total individuals). Each family had two to four affected individuals comprised of either avuncular or cousin pairs. For analysis, we used a high-density single-nucleotide polymorphism genotyping assay, the Affymetrix GeneChip Human Mapping 10K array. Two-point analysis gave peak heterogeneity limit of detection (HLOD) of 2.82 at rs2877739 on chromosome 14q. Suggestive linkage evidence (HLOD>2) from a two-point analysis was also found on chromosomes 1q, 2q, 5q, 6p,11q and 12q. Chromosome 12q was the only region showing significant linkage evidence by multipoint analysis with a peak HLOD=3.02 at rs1445442. In addition, this linkage evidence was enhanced significantly in the families with only male affected (multipoint HLOD=4.51), suggesting a significant gender-specific effect in the etiology of autism. Chromosome-wide haplotype analyses on chromosome 12 localized the potential autism gene to a 4 cM region shared among the affected individuals across linked families. This novel linkage peak on chromosome 12q further supports the hypothesis of substantial locus heterogeneity in autism.
Mol Psychiatry 2007 Apr
PMID:Dissecting the locus heterogeneity of autism: significant linkage to chromosome 12q14. 1717 98

Modern methods that use systematic, quantitative and unbiased approaches are making it possible to discover proteins altered by a disease. To identify proteins that might be differentially expressed in autism, serum proteins from blood were subjected to trypsin digestion followed by liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) on time-of-flight (TOF) instruments to identify differentially expressed peptides. Children with autism 4-6 years of age (n=69) were compared to typically developing children (n=35) with similar age and gender distributions. A total of 6348 peptide components were quantified. Of these, five peptide components corresponding to four known proteins had an effect size >0.99 with a P<0.05 and a Mascot identification score of 30 or greater for autism compared to controls. The four proteins were: Apolipoprotein (apo) B-100, Complement Factor H Related Protein (FHR1), Complement C1q and Fibronectin 1 (FN1). In addition, apo B-100 and apo A-IV were higher in children with high compared to low functioning autism. Apos are involved in the transport of lipids, cholesterol and vitamin E. The complement system is involved in the lysis and removal of infectious organisms in blood, and may be involved in cellular apoptosis in brain. Despite limitations of the study, including the low fold changes and variable detection rates for the peptide components, the data support possible differences of circulating proteins in autism, and should help stimulate the continued search for causes and treatments of autism by examining peripheral blood.
Mol Psychiatry 2007 Mar
PMID:A proteomic study of serum from children with autism showing differential expression of apolipoproteins and complement proteins. 1718 58

The beta2-adrenergic receptor is part of the catecholamine system, and variants at two polymorphic sites in the gene coding for the receptor (ADRB2) confer increased activity. Overstimulation of this receptor may alter brain development, and has been linked to autism in non-identical twins. The objective of this study was to determine whether alleles in ADRB2 are associated with diagnosis of autism in the Autism Genetic Resource Exchange (AGRE) population. Three hundred and thirty-one independent autism case-parent trios were included in the analysis. Subjects were genotyped at activity-related polymorphisms rs1042713 (codon 16) and rs1042714 (codon 27). Association between autism and genotypes at each polymorphic site was tested using genotype-based transmission disequilibrium tests, and effect modification by family and pregnancy characteristics was evaluated. Sensitivity to designation of the proband in each family was assessed by performing 1000 repeats of the analysis selecting affected children randomly. A statistically significant OR of 1.66 for the Glu27 homozygous genotype was observed. Increased associations with this genotype were observed among a subset of Autism Diagnostic Observation Schedule confirmed cases and a subset reporting experience of pregnancy-related stressors. In conclusion, the Glu27 allele of the ADRB2 gene may confer increased risk of autism and shows increased strength with exposure to pregnancy related stress.
Mol Psychiatry 2007 Mar
PMID:beta2-Adrenergic receptor gene variants and risk for autism in the AGRE cohort. 1719 32


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