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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Novel IL1RAPL1 mutations associated with intellectual disability impair synaptogenesis</title><author><name sortKey="Ramos Brossier, Mariana" sort="Ramos Brossier, Mariana" uniqKey="Ramos Brossier M" first="Mariana" last="Ramos-Brossier">Mariana Ramos-Brossier</name><affiliation><nlm:aff id="A1">Institut Cochin<institution>INSERM U1016</institution><institution>CNRS UMR8104</institution><institution>Université Paris Descartes - Paris 5</institution><institution>PRES Sorbonne Paris Cité</institution><addr-line>22 rue Méchain, 75014 Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Montani, Caterina" sort="Montani, Caterina" uniqKey="Montani C" first="Caterina" last="Montani">Caterina Montani</name><affiliation><nlm:aff id="A2">Department of Medical Biotechnology and Translational Medicine<institution>CNR Neuroscience Institute</institution><institution>University of Milan</institution><addr-line>Milan 20129, Italie</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lebrun, Nicolas" sort="Lebrun, Nicolas" uniqKey="Lebrun N" first="Nicolas" last="Lebrun">Nicolas Lebrun</name><affiliation><nlm:aff id="A1">Institut Cochin<institution>INSERM U1016</institution><institution>CNRS UMR8104</institution><institution>Université Paris Descartes - Paris 5</institution><institution>PRES Sorbonne Paris Cité</institution><addr-line>22 rue Méchain, 75014 Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Gritti, Laura" sort="Gritti, Laura" uniqKey="Gritti L" first="Laura" last="Gritti">Laura Gritti</name><affiliation><nlm:aff id="A2">Department of Medical Biotechnology and Translational Medicine<institution>CNR Neuroscience Institute</institution><institution>University of Milan</institution><addr-line>Milan 20129, Italie</addr-line></nlm:aff></affiliation></author><author><name sortKey="Martin, Christelle" sort="Martin, Christelle" uniqKey="Martin C" first="Christelle" last="Martin">Christelle Martin</name><affiliation><nlm:aff id="A3">Interdisciplinary Institute for Neuroscience<institution>Université de Bordeaux</institution><institution>CNRS</institution><addr-line>Bordeaux, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Seminatore Nole, Christine" sort="Seminatore Nole, Christine" uniqKey="Seminatore Nole C" first="Christine" last="Seminatore-Nole">Christine Seminatore-Nole</name><affiliation><nlm:aff id="A1">Institut Cochin<institution>INSERM U1016</institution><institution>CNRS UMR8104</institution><institution>Université Paris Descartes - Paris 5</institution><institution>PRES Sorbonne Paris Cité</institution><addr-line>22 rue Méchain, 75014 Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Toussaint, Aurelie" sort="Toussaint, Aurelie" uniqKey="Toussaint A" first="Aurelie" last="Toussaint">Aurelie Toussaint</name><affiliation><nlm:aff id="A4">Laboratoire de biochimie et génétique moléculaire<institution>Assistance publique - Hôpitaux de Paris (AP-HP)</institution><institution>AP-HP Groupe hospitalier Cochin (Paris)</institution><institution>Université Paris Descartes - Paris 5, France</institution></nlm:aff></affiliation></author><author><name sortKey="Moreno, Sarah" sort="Moreno, Sarah" uniqKey="Moreno S" first="Sarah" last="Moreno">Sarah Moreno</name><affiliation><nlm:aff id="A1">Institut Cochin<institution>INSERM U1016</institution><institution>CNRS UMR8104</institution><institution>Université Paris Descartes - Paris 5</institution><institution>PRES Sorbonne Paris Cité</institution><addr-line>22 rue Méchain, 75014 Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Poirier, Karine" sort="Poirier, Karine" uniqKey="Poirier K" first="Karine" last="Poirier">Karine Poirier</name><affiliation><nlm:aff id="A1">Institut Cochin<institution>INSERM U1016</institution><institution>CNRS UMR8104</institution><institution>Université Paris Descartes - Paris 5</institution><institution>PRES Sorbonne Paris Cité</institution><addr-line>22 rue Méchain, 75014 Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dorseuil, Olivier" sort="Dorseuil, Olivier" uniqKey="Dorseuil O" first="Olivier" last="Dorseuil">Olivier Dorseuil</name><affiliation><nlm:aff id="A1">Institut Cochin<institution>INSERM U1016</institution><institution>CNRS UMR8104</institution><institution>Université Paris Descartes - Paris 5</institution><institution>PRES Sorbonne Paris Cité</institution><addr-line>22 rue Méchain, 75014 Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chelly, Jamel" sort="Chelly, Jamel" uniqKey="Chelly J" first="Jamel" last="Chelly">Jamel Chelly</name><affiliation><nlm:aff id="A1">Institut Cochin<institution>INSERM U1016</institution><institution>CNRS UMR8104</institution><institution>Université Paris Descartes - Paris 5</institution><institution>PRES Sorbonne Paris Cité</institution><addr-line>22 rue Méchain, 75014 Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hackett, Anna" sort="Hackett, Anna" uniqKey="Hackett A" first="Anna" last="Hackett">Anna Hackett</name><affiliation><nlm:aff id="A5">Genetics of Learning Disability Service<institution>Hunter Genetics</institution><addr-line>Waratah, NSW, 2298, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name><affiliation><nlm:aff id="A6">School of Paediatrics and Reproductive Health<institution>Robinson Institute</institution><institution>University of Adelaide</institution><addr-line>Adelaide, SA 5006, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bieth, Eric" sort="Bieth, Eric" uniqKey="Bieth E" first="Eric" last="Bieth">Eric Bieth</name><affiliation><nlm:aff id="A7">Service de Génétique [Purpan]<institution>CHU Toulouse [Toulouse]</institution><institution>Hôpital Purpan</institution><addr-line>Place du Docteur Baylac - TSA 40031 - 31059 Toulouse cedex 9, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Faudet, Anne" sort="Faudet, Anne" uniqKey="Faudet A" first="Anne" last="Faudet">Anne Faudet</name><affiliation><nlm:aff id="A8">Département de Génétique et Cytogénétique<institution>AP-HP Hôpital Universitaire Pitié Salpêtrière (Paris)</institution><addr-line>47-83 Boulevard de l'Hôpital 75013 Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Heron, Delphine" sort="Heron, Delphine" uniqKey="Heron D" first="Delphine" last="Heron">Delphine Heron</name><affiliation><nlm:aff id="A8">Département de Génétique et Cytogénétique<institution>AP-HP Hôpital Universitaire Pitié Salpêtrière (Paris)</institution><addr-line>47-83 Boulevard de l'Hôpital 75013 Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kooy, Frank" sort="Kooy, Frank" uniqKey="Kooy F" first="Frank" last="Kooy">Frank Kooy</name><affiliation><nlm:aff id="A9">Department of Medical Genetics<institution>Faculty of Medicine and Health Sciences</institution><institution> University Hospital Antwerp</institution><addr-line>Antwerp 2610, Belgique</addr-line></nlm:aff></affiliation></author><author><name sortKey="Loeys, Bart" sort="Loeys, Bart" uniqKey="Loeys B" first="Bart" last="Loeys">Bart Loeys</name><affiliation><nlm:aff id="A9">Department of Medical Genetics<institution>Faculty of Medicine and Health Sciences</institution><institution> University Hospital Antwerp</institution><addr-line>Antwerp 2610, Belgique</addr-line></nlm:aff></affiliation></author><author><name sortKey="Humeau, Yann" sort="Humeau, Yann" uniqKey="Humeau Y" first="Yann" last="Humeau">Yann Humeau</name><affiliation><nlm:aff id="A3">Interdisciplinary Institute for Neuroscience<institution>Université de Bordeaux</institution><institution>CNRS</institution><addr-line>Bordeaux, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sala, Carlo" sort="Sala, Carlo" uniqKey="Sala C" first="Carlo" last="Sala">Carlo Sala</name><affiliation><nlm:aff id="A2">Department of Medical Biotechnology and Translational Medicine<institution>CNR Neuroscience Institute</institution><institution>University of Milan</institution><addr-line>Milan 20129, Italie</addr-line></nlm:aff></affiliation></author><author><name sortKey="Billuart, Pierre" sort="Billuart, Pierre" uniqKey="Billuart P" first="Pierre" last="Billuart">Pierre Billuart</name><affiliation><nlm:aff id="A1">Institut Cochin<institution>INSERM U1016</institution><institution>CNRS UMR8104</institution><institution>Université Paris Descartes - Paris 5</institution><institution>PRES Sorbonne Paris Cité</institution><addr-line>22 rue Méchain, 75014 Paris, France</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25305082</idno><idno type="pmc">4867007</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867007</idno><idno type="RBID">PMC:4867007</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">000504</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000504</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Novel IL1RAPL1 mutations associated with intellectual disability impair synaptogenesis</title><author><name sortKey="Ramos Brossier, Mariana" sort="Ramos Brossier, Mariana" uniqKey="Ramos Brossier M" first="Mariana" last="Ramos-Brossier">Mariana Ramos-Brossier</name><affiliation><nlm:aff id="A1">Institut Cochin<institution>INSERM U1016</institution><institution>CNRS UMR8104</institution><institution>Université Paris Descartes - Paris 5</institution><institution>PRES Sorbonne Paris Cité</institution><addr-line>22 rue Méchain, 75014 Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Montani, Caterina" sort="Montani, Caterina" uniqKey="Montani C" first="Caterina" last="Montani">Caterina Montani</name><affiliation><nlm:aff id="A2">Department of Medical Biotechnology and Translational Medicine<institution>CNR Neuroscience Institute</institution><institution>University of Milan</institution><addr-line>Milan 20129, Italie</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lebrun, Nicolas" sort="Lebrun, Nicolas" uniqKey="Lebrun N" first="Nicolas" last="Lebrun">Nicolas Lebrun</name><affiliation><nlm:aff id="A1">Institut Cochin<institution>INSERM U1016</institution><institution>CNRS UMR8104</institution><institution>Université Paris Descartes - Paris 5</institution><institution>PRES Sorbonne Paris Cité</institution><addr-line>22 rue Méchain, 75014 Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Gritti, Laura" sort="Gritti, Laura" uniqKey="Gritti L" first="Laura" last="Gritti">Laura Gritti</name><affiliation><nlm:aff id="A2">Department of Medical Biotechnology and Translational Medicine<institution>CNR Neuroscience Institute</institution><institution>University of Milan</institution><addr-line>Milan 20129, Italie</addr-line></nlm:aff></affiliation></author><author><name sortKey="Martin, Christelle" sort="Martin, Christelle" uniqKey="Martin C" first="Christelle" last="Martin">Christelle Martin</name><affiliation><nlm:aff id="A3">Interdisciplinary Institute for Neuroscience<institution>Université de Bordeaux</institution><institution>CNRS</institution><addr-line>Bordeaux, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Seminatore Nole, Christine" sort="Seminatore Nole, Christine" uniqKey="Seminatore Nole C" first="Christine" last="Seminatore-Nole">Christine Seminatore-Nole</name><affiliation><nlm:aff id="A1">Institut Cochin<institution>INSERM U1016</institution><institution>CNRS UMR8104</institution><institution>Université Paris Descartes - Paris 5</institution><institution>PRES Sorbonne Paris Cité</institution><addr-line>22 rue Méchain, 75014 Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Toussaint, Aurelie" sort="Toussaint, Aurelie" uniqKey="Toussaint A" first="Aurelie" last="Toussaint">Aurelie Toussaint</name><affiliation><nlm:aff id="A4">Laboratoire de biochimie et génétique moléculaire<institution>Assistance publique - Hôpitaux de Paris (AP-HP)</institution><institution>AP-HP Groupe hospitalier Cochin (Paris)</institution><institution>Université Paris Descartes - Paris 5, France</institution></nlm:aff></affiliation></author><author><name sortKey="Moreno, Sarah" sort="Moreno, Sarah" uniqKey="Moreno S" first="Sarah" last="Moreno">Sarah Moreno</name><affiliation><nlm:aff id="A1">Institut Cochin<institution>INSERM U1016</institution><institution>CNRS UMR8104</institution><institution>Université Paris Descartes - Paris 5</institution><institution>PRES Sorbonne Paris Cité</institution><addr-line>22 rue Méchain, 75014 Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Poirier, Karine" sort="Poirier, Karine" uniqKey="Poirier K" first="Karine" last="Poirier">Karine Poirier</name><affiliation><nlm:aff id="A1">Institut Cochin<institution>INSERM U1016</institution><institution>CNRS UMR8104</institution><institution>Université Paris Descartes - Paris 5</institution><institution>PRES Sorbonne Paris Cité</institution><addr-line>22 rue Méchain, 75014 Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dorseuil, Olivier" sort="Dorseuil, Olivier" uniqKey="Dorseuil O" first="Olivier" last="Dorseuil">Olivier Dorseuil</name><affiliation><nlm:aff id="A1">Institut Cochin<institution>INSERM U1016</institution><institution>CNRS UMR8104</institution><institution>Université Paris Descartes - Paris 5</institution><institution>PRES Sorbonne Paris Cité</institution><addr-line>22 rue Méchain, 75014 Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chelly, Jamel" sort="Chelly, Jamel" uniqKey="Chelly J" first="Jamel" last="Chelly">Jamel Chelly</name><affiliation><nlm:aff id="A1">Institut Cochin<institution>INSERM U1016</institution><institution>CNRS UMR8104</institution><institution>Université Paris Descartes - Paris 5</institution><institution>PRES Sorbonne Paris Cité</institution><addr-line>22 rue Méchain, 75014 Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hackett, Anna" sort="Hackett, Anna" uniqKey="Hackett A" first="Anna" last="Hackett">Anna Hackett</name><affiliation><nlm:aff id="A5">Genetics of Learning Disability Service<institution>Hunter Genetics</institution><addr-line>Waratah, NSW, 2298, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name><affiliation><nlm:aff id="A6">School of Paediatrics and Reproductive Health<institution>Robinson Institute</institution><institution>University of Adelaide</institution><addr-line>Adelaide, SA 5006, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bieth, Eric" sort="Bieth, Eric" uniqKey="Bieth E" first="Eric" last="Bieth">Eric Bieth</name><affiliation><nlm:aff id="A7">Service de Génétique [Purpan]<institution>CHU Toulouse [Toulouse]</institution><institution>Hôpital Purpan</institution><addr-line>Place du Docteur Baylac - TSA 40031 - 31059 Toulouse cedex 9, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Faudet, Anne" sort="Faudet, Anne" uniqKey="Faudet A" first="Anne" last="Faudet">Anne Faudet</name><affiliation><nlm:aff id="A8">Département de Génétique et Cytogénétique<institution>AP-HP Hôpital Universitaire Pitié Salpêtrière (Paris)</institution><addr-line>47-83 Boulevard de l'Hôpital 75013 Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Heron, Delphine" sort="Heron, Delphine" uniqKey="Heron D" first="Delphine" last="Heron">Delphine Heron</name><affiliation><nlm:aff id="A8">Département de Génétique et Cytogénétique<institution>AP-HP Hôpital Universitaire Pitié Salpêtrière (Paris)</institution><addr-line>47-83 Boulevard de l'Hôpital 75013 Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kooy, Frank" sort="Kooy, Frank" uniqKey="Kooy F" first="Frank" last="Kooy">Frank Kooy</name><affiliation><nlm:aff id="A9">Department of Medical Genetics<institution>Faculty of Medicine and Health Sciences</institution><institution> University Hospital Antwerp</institution><addr-line>Antwerp 2610, Belgique</addr-line></nlm:aff></affiliation></author><author><name sortKey="Loeys, Bart" sort="Loeys, Bart" uniqKey="Loeys B" first="Bart" last="Loeys">Bart Loeys</name><affiliation><nlm:aff id="A9">Department of Medical Genetics<institution>Faculty of Medicine and Health Sciences</institution><institution> University Hospital Antwerp</institution><addr-line>Antwerp 2610, Belgique</addr-line></nlm:aff></affiliation></author><author><name sortKey="Humeau, Yann" sort="Humeau, Yann" uniqKey="Humeau Y" first="Yann" last="Humeau">Yann Humeau</name><affiliation><nlm:aff id="A3">Interdisciplinary Institute for Neuroscience<institution>Université de Bordeaux</institution><institution>CNRS</institution><addr-line>Bordeaux, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sala, Carlo" sort="Sala, Carlo" uniqKey="Sala C" first="Carlo" last="Sala">Carlo Sala</name><affiliation><nlm:aff id="A2">Department of Medical Biotechnology and Translational Medicine<institution>CNR Neuroscience Institute</institution><institution>University of Milan</institution><addr-line>Milan 20129, Italie</addr-line></nlm:aff></affiliation></author><author><name sortKey="Billuart, Pierre" sort="Billuart, Pierre" uniqKey="Billuart P" first="Pierre" last="Billuart">Pierre Billuart</name><affiliation><nlm:aff id="A1">Institut Cochin<institution>INSERM U1016</institution><institution>CNRS UMR8104</institution><institution>Université Paris Descartes - Paris 5</institution><institution>PRES Sorbonne Paris Cité</institution><addr-line>22 rue Méchain, 75014 Paris, France</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">Human Molecular Genetics</title><idno type="ISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P2">Mutations in interleukin-1 receptor accessory protein like 1 (<italic>IL1RAPL1</italic>) gene have been associated with non-syndromic intellectual disability and autism spectrum disorder. This protein interacts with synaptic partners like PSD-95 and PTPδ, regulating the formation and function of excitatory synapses. The aim of this work is to characterize the synaptic consequences of three <italic>IL1RAPL1</italic> mutations, two novel causing the deletion of exon 6 (Δex6) and one point mutation (C31R), identified in patients with intellectual disability. Using immunofluorescence and electrophysiological recordings we examined the effects of IL1RAPL1 mutants over-expression on synapse formation and function in cultured rodent hippocampal neurons. Δex6 but not C31R mutation leads to IL1RAPL1 protein instability and mislocalization within dendrites. Analysis of different markers of excitatory synapses and sEPSC recording revealed that both mutants fail to induce pre- and post-synaptic differentiation, contrary to WT IL1RAPL1 protein. Cell aggregation and immunoprecipitation assays in HEK293 cells showed a reduction of the interaction between IL1RAPL1 mutants and PTPδ that could explain the observed synaptogenic defect in neurons. However, these mutants do not affect all cellular signaling since their over-expression still activates JNK pathway. We conclude that both mutations described in this study lead to a partial loss of function of the IL1RAPL1 protein through different mechanisms. Our work highlights the important function of the trans-synaptic PTPδ/ IL1RAPL1 interaction in synaptogenesis and as such, in intellectual disability in the patients.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
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<front><journal-meta><journal-id journal-id-type="nlm-ta">Hum Mol Genet</journal-id><journal-id journal-id-type="iso-abbrev">Hum. Mol. Genet</journal-id><journal-title-group><journal-title>Human Molecular Genetics</journal-title></journal-title-group><issn pub-type="ppub">0964-6906</issn><issn pub-type="epub">1460-2083</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">25305082</article-id><article-id pub-id-type="pmc">4867007</article-id><article-id pub-id-type="publisher-manuscript">inserm-01102927</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject><subj-group subj-group-type="subrepository"><subject>INSERM Subrepository</subject></subj-group></subj-group></article-categories><title-group><article-title>Novel IL1RAPL1 mutations associated with intellectual disability impair synaptogenesis</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Ramos-Brossier</surname><given-names>Mariana</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Montani</surname><given-names>Caterina</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Lebrun</surname><given-names>Nicolas</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Gritti</surname><given-names>Laura</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Martin</surname><given-names>Christelle</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Seminatore-Nole</surname><given-names>Christine</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Toussaint</surname><given-names>Aurelie</given-names></name><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Moreno</surname><given-names>Sarah</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Poirier</surname><given-names>Karine</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Dorseuil</surname><given-names>Olivier</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Chelly</surname><given-names>Jamel</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Hackett</surname><given-names>Anna</given-names></name><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Gecz</surname><given-names>Jozef</given-names></name><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Bieth</surname><given-names>Eric</given-names></name><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Faudet</surname><given-names>Anne</given-names></name><xref ref-type="aff" rid="A8">8</xref></contrib><contrib contrib-type="author"><name><surname>Heron</surname><given-names>Delphine</given-names></name><xref ref-type="aff" rid="A8">8</xref></contrib><contrib contrib-type="author"><name><surname>Kooy</surname><given-names>Frank</given-names></name><xref ref-type="aff" rid="A9">9</xref></contrib><contrib contrib-type="author"><name><surname>Loeys</surname><given-names>Bart</given-names></name><xref ref-type="aff" rid="A9">9</xref></contrib><contrib contrib-type="author"><name><surname>Humeau</surname><given-names>Yann</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Sala</surname><given-names>Carlo</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Billuart</surname><given-names>Pierre</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref rid="FN1" ref-type="author-notes">*</xref></contrib></contrib-group><aff id="A1"><label>1</label>Institut Cochin<institution>INSERM U1016</institution><institution>CNRS UMR8104</institution><institution>Université Paris Descartes - Paris 5</institution><institution>PRES Sorbonne Paris Cité</institution><addr-line>22 rue Méchain, 75014 Paris, France</addr-line></aff><aff id="A2"><label>2</label>Department of Medical Biotechnology and Translational Medicine<institution>CNR Neuroscience Institute</institution><institution>University of Milan</institution><addr-line>Milan 20129, Italie</addr-line></aff><aff id="A3"><label>3</label>Interdisciplinary Institute for Neuroscience<institution>Université de Bordeaux</institution><institution>CNRS</institution><addr-line>Bordeaux, France</addr-line></aff><aff id="A4"><label>4</label>Laboratoire de biochimie et génétique moléculaire<institution>Assistance publique - Hôpitaux de Paris (AP-HP)</institution><institution>AP-HP Groupe hospitalier Cochin (Paris)</institution><institution>Université Paris Descartes - Paris 5, France</institution></aff><aff id="A5"><label>5</label>Genetics of Learning Disability Service<institution>Hunter Genetics</institution><addr-line>Waratah, NSW, 2298, Australia</addr-line></aff><aff id="A6"><label>6</label>School of Paediatrics and Reproductive Health<institution>Robinson Institute</institution><institution>University of Adelaide</institution><addr-line>Adelaide, SA 5006, Australia</addr-line></aff><aff id="A7"><label>7</label>Service de Génétique [Purpan]<institution>CHU Toulouse [Toulouse]</institution><institution>Hôpital Purpan</institution><addr-line>Place du Docteur Baylac - TSA 40031 - 31059 Toulouse cedex 9, France</addr-line></aff><aff id="A8"><label>8</label>Département de Génétique et Cytogénétique<institution>AP-HP Hôpital Universitaire Pitié Salpêtrière (Paris)</institution><addr-line>47-83 Boulevard de l'Hôpital 75013 Paris, France</addr-line></aff><aff id="A9"><label>9</label>Department of Medical Genetics<institution>Faculty of Medicine and Health Sciences</institution><institution> University Hospital Antwerp</institution><addr-line>Antwerp 2610, Belgique</addr-line></aff><author-notes><corresp id="FN1">* Correspondence should be addressed to Pierre Billuart <email>pierre.billuart@inserm.fr</email></corresp></author-notes><pub-date pub-type="ppub"><month>2</month><year>2015</year></pub-date><pub-date pub-type="epub"><day>09</day><month>10</month><year>2014</year></pub-date><fpage>523</fpage><lpage>523</lpage><abstract><p id="P2">Mutations in interleukin-1 receptor accessory protein like 1 (<italic>IL1RAPL1</italic>) gene have been associated with non-syndromic intellectual disability and autism spectrum disorder. This protein interacts with synaptic partners like PSD-95 and PTPδ, regulating the formation and function of excitatory synapses. The aim of this work is to characterize the synaptic consequences of three <italic>IL1RAPL1</italic> mutations, two novel causing the deletion of exon 6 (Δex6) and one point mutation (C31R), identified in patients with intellectual disability. Using immunofluorescence and electrophysiological recordings we examined the effects of IL1RAPL1 mutants over-expression on synapse formation and function in cultured rodent hippocampal neurons. Δex6 but not C31R mutation leads to IL1RAPL1 protein instability and mislocalization within dendrites. Analysis of different markers of excitatory synapses and sEPSC recording revealed that both mutants fail to induce pre- and post-synaptic differentiation, contrary to WT IL1RAPL1 protein. Cell aggregation and immunoprecipitation assays in HEK293 cells showed a reduction of the interaction between IL1RAPL1 mutants and PTPδ that could explain the observed synaptogenic defect in neurons. However, these mutants do not affect all cellular signaling since their over-expression still activates JNK pathway. We conclude that both mutations described in this study lead to a partial loss of function of the IL1RAPL1 protein through different mechanisms. Our work highlights the important function of the trans-synaptic PTPδ/ IL1RAPL1 interaction in synaptogenesis and as such, in intellectual disability in the patients.</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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