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  • 1
    Keywords: EXPRESSION ; CELL ; Germany ; CLONES ; GENE ; GENE-EXPRESSION ; GENES ; GENOME ; HYBRIDIZATION ; PROTEIN ; RNA ; DIFFERENTIATION ; LINES ; PATIENT ; FAMILY ; DOMAIN ; CELL-LINES ; MEMBERS ; DELETION ; IN-SITU ; chromosome 2 ; COMPARATIVE GENOMIC HYBRIDIZATION ; gene expression ; genetics ; PHENOTYPE ; SERINE/THREONINE KINASE ; INDIVIDUALS ; cell lines ; FAMILIES ; CANDIDATE GENES ; NEURONS ; autism ; USA ; EXTENT ; rho GTPases ; Genetic ; ALBRIGHT HEREDITARY OSTEODYSTROPHY ; COGNITIVE FUNCTION ; Lymphoblastoid cell lines ; terminal deletion 2q
    Abstract: We describe a patient with autism and brachymetaphalangy, meeting criteria for 2q37 deletion syndrome (also called Albright Hereditary Osteodystrophy-like syndrome or Brachydactyly-Mental Retardation syndrome, OMIM 600430). Our molecular cytogenetic studies, including array comparative genomic hybridization (aCGH) and fluorescence in situ hybridization (FISH), define the extent of the de novo deletion to a 3.5 Mb region on 2q37.3. Although a number of reports of patients with 2q37 deletion syndrome have been published, it remains unclear if gene expression and/or translation are altered by the deletion, thus contributing to the observed phenotypes. To address this question, we selected several candidate genes for the neuropsychiatric and skeletal anomalies found in this patient (autism and brachymetaphalangy). The deleted region in 2q37.3 includes the FERM, RhoGEF and pleckstrin domain protein 2 (FARF2), glypican 1 (GPC1), vigilin (HDLBP), kinesin family member 1A (KIFIA) and proline-alanine-rich STE20-related kinase (PASK), all of which are involved in skeletal or neural differentiation processes. Expression analyses of these genes were performed using RNA from lymphoblastoid cell lines of the patient and his familly members. Here we demonstrate that three of these genes, FARP2, HDLBP, and PASK, are considerably downregulated in the patient's cell line. We hypothesize that haploinsufficiency of these genes may have contributed to the patient's clinical phenotype. (c) 2009 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 19365831
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  • 2
    Keywords: SPECTRA ; RISK ; GENE ; GENES ; SAMPLES ; COMPLEX ; COMPLEXES ; FAMILY ; ASSOCIATION ; chromosome ; LINKAGE ; NUMBER ; SNP ; HUMAN GENOME ; TWIN ; PREVALENCE ; DISSECTION ; GLUTAMATE ; FAMILIES ; ARRAY ; REARRANGEMENT ; CANDIDATE ; SPECTRUM ; MENTAL-RETARDATION ; LOCI ; NEUROLIGINS ; SPECTRUM DISORDERS
    Abstract: Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,168 families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs
    Type of Publication: Journal article published
    PubMed ID: 17322880
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  • 3
    Keywords: RECEPTOR ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; proliferation ; tumor ; FACTOR RECEPTOR ; INHIBITION ; MODEL ; PATHWAY ; PATHWAYS ; DISEASE ; liver ; GENE ; GENES ; transcription ; MICE ; TUMOR-NECROSIS-FACTOR ; DOWN-REGULATION ; GROWTH-FACTOR RECEPTOR ; ALPHA ; ACID ; MOUSE ; resistance ; INDUCED APOPTOSIS ; UP-REGULATION ; NECROSIS-FACTOR-ALPHA ; inactivation ; DAMAGE ; SIGNALING PATHWAY ; SIGNALING PATHWAYS ; PHENOTYPE ; MOUSE MODEL ; INJURY ; EPIDERMAL-GROWTH-FACTOR ; INCREASED EXPRESSION ; signaling ; CYTOKINE ; FAS ; BILE ; INTERLEUKIN-6 ; KNOCKOUT MICE ; methods ; BARRIER ; NECROSIS ; Stat3 ; CHOLESTASIS ; interleukin 6 ; FACTOR-RECEPTOR ; Conditional mouse model ; BILE-ACIDS ; PRIMARY HEPATOCYTES
    Abstract: BACKGROUND & AIMS: Signal transducer and activator of transcription 3 (Stat3) is the main mediator of interleukin-6-type cytokine signaling required for hepatocyte proliferation and hepatoprotection, but its role in sclerosing cholangitis and other cholestatic liver diseases remains unresolved. METHODS: We investigated the role of Stat3 in inflammation-induced cholestatic liver injury and used mice lacking the multidrug resistance gene 2 (mdr2(-/-)) as a model for SC. RESULTS: We show that conditional inactivation of Stat3 in hepatocytes and cholangiocytes (stat3(Delta hc)) of mdr2(-/-) mice strongly aggravated bile acid-induced liver injury and fibrosis. A similar phenotype was observed in mdr2(-/-) mice lacking interleukin-6 production. Biochemical and molecular characterization suggested that Stat3 exerts hepatoprotective functions in both hepatocytes and cholangiocytes. Loss of Stat3 led to increased expression of tumor necrosis factor alpha, which might reduce the barrier function of bile ducts. Moreover, Stat3-deficient hepatocytes displayed up-regulation of bile acid biosynthesis genes and down-regulation of hepatoprotective epidermal growth factor receptor and insulin-like growth factor 1 signaling pathways. Consistently, stat3(Delta hc) mice were more sensitive to cholic acid-induced liver damage than control mice. CONCLUSIONS: Our data suggest that Stat3 prevents cholestasis and liver damage in sclerosing cholangitis via regulation of pivotal functions in hepatocytes and cholangiocytes
    Type of Publication: Journal article published
    PubMed ID: 20193684
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  • 4
    Keywords: brain ; EXPRESSION ; Germany ; MODEL ; SYSTEM ; DISEASE ; GENE ; GENES ; GENOME ; HYBRIDIZATION ; PROTEIN ; RNA ; SACCHAROMYCES-CEREVISIAE ; MECHANISM ; FAMILY ; IMPACT ; BIOLOGY ; chromosome ; FREQUENCY ; GENOMEWIDE SCREEN ; FREQUENCIES ; hippocampus ; MOUSE ; IN-SITU ; MUTATION ; etiology ; MUTATIONS ; PERVASIVE DEVELOPMENTAL DISORDERS ; INVOLVEMENT ; INDIVIDUALS ; in situ hybridization ; FAMILIES ; TRANSLATION ; MISSENSE MUTATION ; autism ; function ; Male ; SPECTRUM ; SUBSTITUTION ; AMINO-ACID SUBSTITUTIONS ; autistic disorder ; PROTEIN GENE ; ribosomal protein ; SEROTONIN TRANSPORTER 5-HTT ; SUBUNIT PROTEIN ; X MENTAL-RETARDATION ; Xq28
    Abstract: 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
    Type of Publication: Journal article published
    PubMed ID: 16940977
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