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  • 1
    Keywords: EXPRESSION ; MESSENGER-RNA ; TRANSLATION ; MENTAL-RETARDATION PROTEIN ; METABOTROPIC GLUTAMATE RECEPTORS ; GENOME-WIDE ASSOCIATION ; FRAGILE-X-SYNDROME ; DIAGNOSTIC INTERVIEW ; PROTEIN-KINASE-IV ; GERMAN FORM
    Abstract: Autism spectrum disorders (ASD) are heterogeneous disorders with a high heritability and complex genetic architecture. Due to the central role of the fragile X mental retardation gene 1 protein (FMRP) pathway in ASD we investigated common functional variants of ASD risk genes regulating FMRP. We genotyped ten SNPs in two German patient sets (N = 192 and N = 254 families, respectively) and report association for rs7170637 (CYFIP1; set 1 and combined sets), rs6923492 (GRM1; combined sets), and rs25925 (CAMK4; combined sets). An additional risk score based on variants with an odds ratio (OR) 〉1.25 in set 1 and weighted by their respective log transmitted/untransmitted ratio revealed a significant effect (OR 1.30, 95 % CI 1.11-1.53; P = 0.0013) in the combined German sample. A subsequent meta-analysis including the two German samples, the "Strict/European" ASD subsample of the Autism Genome Project (1,466 families) and a French case/control (541/366) cohort showed again association of rs7170637-A (OR 0.85, 95 % CI 0.75-0.96; P = 0.007) and rs25925-G (OR 1.31, 95 % CI 1.04-1.64; P = 0.021) with ASD. Functional analyses revealed that these minor alleles predicted to alter splicing factor binding sites significantly increase levels of an alternative mRNA isoform of the respective gene while keeping the overall expression of the gene constant. These findings underpin the role of ASD candidate genes in postsynaptic FMRP regulation suggesting that an imbalance of specific isoforms of CYFIP1, an FMRP interaction partner, and CAMK4, a transcriptional regulator of the FMRP gene, modulates ASD risk. Both gene products are related to neuronal regulation of synaptic plasticity, a pathomechanism underlying ASD and may thus present future targets for pharmacological therapies in ASD.
    Type of Publication: Journal article published
    PubMed ID: 24442360
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  • 2
    Keywords: MODEL ; GENE ; DELETION ; MUTATIONS ; PSYCHIATRIC-DISORDERS ; MENTAL-RETARDATION ; COPY-NUMBER VARIATION ; HIDDEN-MARKOV MODEL ; SNP GENOTYPING DATA ; 15Q13.3 MICRODELETIONS ; DE-NOVO MUTATIONS ; POSTSYNAPTIC DENSITY ; RECURRENT MICRODELETIONS ; SCAFFOLDING PROTEIN SHANK3
    Abstract: Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model" for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.
    Type of Publication: Journal article published
    PubMed ID: 22346768
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  • 3
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Journal of Invertebrate Pathology 59 (1992), S. 11-17 
    ISSN: 0022-2011
    Keywords: Hirudinea ; Hirudo medicinalis ; annelid ; epithelium ; wound healing
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    New York, NY : Wiley-Blackwell
    Journal of Morphology 216 (1993), S. 295-304 
    ISSN: 0362-2525
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: The ultrastructure and histochemical features of the two types of secretory cells in leech skin are described. Pear-shaped cells secrete mucus containing carboxylated mucosubstances, while tubular cells produce a mucus containing a mixture of neutral, carboxylated, and sulfated mucosubstances. Pear-shaped secretory cells have two types of neuroglandular junctions, one containing dense-core serotonergic vesicles and the other small clear vesicles. Tubular secretory cells have large terminals, with many clear vesicles thought to be cholinergic. © 1993 Wiley-Liss, Inc.
    Additional Material: 13 Ill.
    Type of Medium: Electronic Resource
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  • 5
    Publication Date: 2014-05-30
    Description: Although considerable evidence suggests that the chemical synapse is a lynchpin underlying affective disorders, how molecular insults differentially affect specific synaptic connections remains poorly understood. For instance, Neurexin 1a and 2 (NRXN1 and NRXN2) and CNTNAP2 (also known as CASPR2), all members of the neurexin superfamily of transmembrane molecules, have been implicated in neuropsychiatric disorders. However, their loss leads to deficits that have been best characterized with regard to their effect on excitatory cells. Notably, other disease-associated genes such as BDNF and ERBB4 implicate specific interneuron synapses in psychiatric disorders. Consistent with this, cortical interneuron dysfunction has been linked to epilepsy, schizophrenia and autism. Using a microarray screen that focused upon synapse-associated molecules, we identified Cntnap4 (contactin associated protein-like 4, also known as Caspr4) as highly enriched in developing murine interneurons. In this study we show that Cntnap4 is localized presynaptically and its loss leads to a reduction in the output of cortical parvalbumin (PV)-positive GABAergic (gamma-aminobutyric acid producing) basket cells. Paradoxically, the loss of Cntnap4 augments midbrain dopaminergic release in the nucleus accumbens. In Cntnap4 mutant mice, synaptic defects in these disease-relevant neuronal populations are mirrored by sensory-motor gating and grooming endophenotypes; these symptoms could be pharmacologically reversed, providing promise for therapeutic intervention in psychiatric disorders.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281262/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281262/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Karayannis, T -- Au, E -- Patel, J C -- Kruglikov, I -- Markx, S -- Delorme, R -- Heron, D -- Salomon, D -- Glessner, J -- Restituito, S -- Gordon, A -- Rodriguez-Murillo, L -- Roy, N C -- Gogos, J A -- Rudy, B -- Rice, M E -- Karayiorgou, M -- Hakonarson, H -- Keren, B -- Huguet, G -- Bourgeron, T -- Hoeffer, C -- Tsien, R W -- Peles, E -- Fishell, G -- NS30989/NS/NINDS NIH HHS/ -- NS50220/NS/NINDS NIH HHS/ -- P01 NS074972/NS/NINDS NIH HHS/ -- R01 DA033811/DA/NIDA NIH HHS/ -- R01 MH071679/MH/NIMH NIH HHS/ -- R01 NS030989/NS/NINDS NIH HHS/ -- R01 NS036362/NS/NINDS NIH HHS/ -- R01 NS050220/NS/NINDS NIH HHS/ -- R01 NS074972/NS/NINDS NIH HHS/ -- R01 NS081297/NS/NINDS NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2014 Jul 10;511(7508):236-40.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24870235" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antipsychotic Agents/pharmacology ; Behavior, Animal/drug effects/physiology ; Dopamine/*metabolism ; Electrical Synapses/genetics/ultrastructure ; Female ; Genotype ; Humans ; Male ; Membrane Proteins/*genetics/*metabolism ; Mice ; Nerve Tissue Proteins/*genetics/*metabolism ; Polymorphism, Single Nucleotide ; *Signal Transduction ; Synaptic Transmission/*genetics ; gamma-Aminobutyric Acid/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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