AustralieFrV1, Main, Exploration, bibRecord, 003676

Novel IL1RAPL1 mutations associated with intellectual disability impair synaptogenesis

Identifieur interne : 003676 ( Main/Exploration ); précédent : 003675; suivant : 003677

Novel IL1RAPL1 mutations associated with intellectual disability impair synaptogenesis

Auteurs : Mariana Ramos-Brossier [France] ; Caterina Montani [Italie] ; Nicolas Lebrun [France] ; Laura Gritti [Italie] ; Christelle Martin [France] ; Christine Seminatore-Nole [France] ; Aurelie Toussaint ; Sarah Moreno [France] ; Karine Poirier [France] ; Olivier Dorseuil [France] ; Jamel Chelly [France] ; Anna Hackett [Australie] ; Jozef Gecz [Australie] ; Eric Bieth [France] ; Anne Faudet [France] ; Delphine Heron [France] ; Frank Kooy [Belgique] ; Bart Loeys [Belgique] ; Yann Humeau [France] ; Carlo Sala [Italie] ; Pierre Billuart [France]

Source :

Human Molecular Genetics [ 0964-6906 ] ; 2014.

RBID : PMC:4867007

Descripteurs français

English descriptors

KwdEn :
- Adult, Child, Child, Preschool, DNA Mutational Analysis, Exons, Female, Humans, Intellectual Disability (genetics), Intellectual Disability (metabolism), Interleukin-1 Receptor Accessory Protein (chemistry), Interleukin-1 Receptor Accessory Protein (genetics), Interleukin-1 Receptor Accessory Protein (metabolism), Introns, Male, Mutation, Neurogenesis (genetics), Pedigree, Polymorphism, Single Nucleotide, Protein Interaction Domains and Motifs, Protein Transport, Sequence Deletion, Signal Transduction, Synapses (genetics), Synapses (metabolism).
MESH :
- chemical , chemistry : Interleukin-1 Receptor Accessory Protein.
- genetics : Intellectual Disability, Interleukin-1 Receptor Accessory Protein, Neurogenesis, Synapses.
- metabolism : Intellectual Disability, Interleukin-1 Receptor Accessory Protein, Synapses.
- Adult, Child, Child, Preschool, DNA Mutational Analysis, Exons, Female, Humans, Introns, Male, Mutation, Pedigree, Polymorphism, Single Nucleotide, Protein Interaction Domains and Motifs, Protein Transport, Sequence Deletion, Signal Transduction.

Abstract

Mutations in interleukin-1 receptor accessory protein like 1 (IL1RAPL1) 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 IL1RAPL1 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.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867007

PubMed: 25305082
PubMed Central: 4867007

Affiliations:

Le document en format XML

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<author><name sortKey="Moreno, Sarah" sort="Moreno, Sarah" uniqKey="Moreno S" first="Sarah" last="Moreno">Sarah Moreno</name>
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<author><name sortKey="Chelly, Jamel" sort="Chelly, Jamel" uniqKey="Chelly J" first="Jamel" last="Chelly">Jamel Chelly</name>
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<institution>CNRS UMR8104</institution>
<institution>Université Paris Descartes - Paris 5</institution>
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<addr-line>Waratah, NSW, 2298, Australia</addr-line>
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<author><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name>
<affiliation wicri:level="1"><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>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Adelaide, SA 5006</wicri:regionArea>
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<author><name sortKey="Bieth, Eric" sort="Bieth, Eric" uniqKey="Bieth E" first="Eric" last="Bieth">Eric Bieth</name>
<affiliation wicri:level="1"><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>
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<author><name sortKey="Faudet, Anne" sort="Faudet, Anne" uniqKey="Faudet A" first="Anne" last="Faudet">Anne Faudet</name>
<affiliation wicri:level="1"><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>
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<author><name sortKey="Heron, Delphine" sort="Heron, Delphine" uniqKey="Heron D" first="Delphine" last="Heron">Delphine Heron</name>
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<addr-line>47-83 Boulevard de l'Hôpital 75013 Paris, France</addr-line>
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<author><name sortKey="Kooy, Frank" sort="Kooy, Frank" uniqKey="Kooy F" first="Frank" last="Kooy">Frank Kooy</name>
<affiliation wicri:level="1"><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>
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<country xml:lang="fr">Belgique</country>
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<author><name sortKey="Loeys, Bart" sort="Loeys, Bart" uniqKey="Loeys B" first="Bart" last="Loeys">Bart Loeys</name>
<affiliation wicri:level="1"><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>
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<wicri:regionArea>Antwerp 2610</wicri:regionArea>
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<author><name sortKey="Humeau, Yann" sort="Humeau, Yann" uniqKey="Humeau Y" first="Yann" last="Humeau">Yann Humeau</name>
<affiliation wicri:level="1"><nlm:aff id="A3">Interdisciplinary Institute for Neuroscience<institution>Université de Bordeaux</institution>
<institution>CNRS</institution>
<addr-line>Bordeaux, France</addr-line>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Bordeaux</wicri:regionArea>
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</author>
<author><name sortKey="Sala, Carlo" sort="Sala, Carlo" uniqKey="Sala C" first="Carlo" last="Sala">Carlo Sala</name>
<affiliation wicri:level="1"><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>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Milan 20129</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Billuart, Pierre" sort="Billuart, Pierre" uniqKey="Billuart P" first="Pierre" last="Billuart">Pierre Billuart</name>
<affiliation wicri:level="1"><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>
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<country xml:lang="fr">France</country>
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<wicri:noRegion>75014 Paris</wicri:noRegion>
<placeName><settlement type="city">Paris</settlement>
<region type="région" nuts="2">Île-de-France</region>
</placeName>
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</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>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adult</term>
<term>Child</term>
<term>Child, Preschool</term>
<term>DNA Mutational Analysis</term>
<term>Exons</term>
<term>Female</term>
<term>Humans</term>
<term>Intellectual Disability (genetics)</term>
<term>Intellectual Disability (metabolism)</term>
<term>Interleukin-1 Receptor Accessory Protein (chemistry)</term>
<term>Interleukin-1 Receptor Accessory Protein (genetics)</term>
<term>Interleukin-1 Receptor Accessory Protein (metabolism)</term>
<term>Introns</term>
<term>Male</term>
<term>Mutation</term>
<term>Neurogenesis (genetics)</term>
<term>Pedigree</term>
<term>Polymorphism, Single Nucleotide</term>
<term>Protein Interaction Domains and Motifs</term>
<term>Protein Transport</term>
<term>Sequence Deletion</term>
<term>Signal Transduction</term>
<term>Synapses (genetics)</term>
<term>Synapses (metabolism)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Adulte</term>
<term>Analyse de mutations d'ADN</term>
<term>Déficience intellectuelle (génétique)</term>
<term>Déficience intellectuelle (métabolisme)</term>
<term>Délétion de séquence</term>
<term>Enfant</term>
<term>Enfant d'âge préscolaire</term>
<term>Exons</term>
<term>Femelle</term>
<term>Humains</term>
<term>Introns</term>
<term>Motifs et domaines d'intéraction protéique</term>
<term>Mutation</term>
<term>Mâle</term>
<term>Neurogenèse (génétique)</term>
<term>Pedigree</term>
<term>Polymorphisme de nucléotide simple</term>
<term>Protéine accessoire du récepteur à l'interleukine-1 ()</term>
<term>Protéine accessoire du récepteur à l'interleukine-1 (génétique)</term>
<term>Protéine accessoire du récepteur à l'interleukine-1 (métabolisme)</term>
<term>Synapses (génétique)</term>
<term>Synapses (métabolisme)</term>
<term>Transduction du signal</term>
<term>Transport de protéines</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Interleukin-1 Receptor Accessory Protein</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Intellectual Disability</term>
<term>Interleukin-1 Receptor Accessory Protein</term>
<term>Neurogenesis</term>
<term>Synapses</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Déficience intellectuelle</term>
<term>Neurogenèse</term>
<term>Protéine accessoire du récepteur à l'interleukine-1</term>
<term>Synapses</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Intellectual Disability</term>
<term>Interleukin-1 Receptor Accessory Protein</term>
<term>Synapses</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Déficience intellectuelle</term>
<term>Protéine accessoire du récepteur à l'interleukine-1</term>
<term>Synapses</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Adult</term>
<term>Child</term>
<term>Child, Preschool</term>
<term>DNA Mutational Analysis</term>
<term>Exons</term>
<term>Female</term>
<term>Humans</term>
<term>Introns</term>
<term>Male</term>
<term>Mutation</term>
<term>Pedigree</term>
<term>Polymorphism, Single Nucleotide</term>
<term>Protein Interaction Domains and Motifs</term>
<term>Protein Transport</term>
<term>Sequence Deletion</term>
<term>Signal Transduction</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Adulte</term>
<term>Analyse de mutations d'ADN</term>
<term>Délétion de séquence</term>
<term>Enfant</term>
<term>Enfant d'âge préscolaire</term>
<term>Exons</term>
<term>Femelle</term>
<term>Humains</term>
<term>Introns</term>
<term>Motifs et domaines d'intéraction protéique</term>
<term>Mutation</term>
<term>Mâle</term>
<term>Pedigree</term>
<term>Polymorphisme de nucléotide simple</term>
<term>Protéine accessoire du récepteur à l'interleukine-1</term>
<term>Transduction du signal</term>
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<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>
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<tree><noCountry><name sortKey="Toussaint, Aurelie" sort="Toussaint, Aurelie" uniqKey="Toussaint A" first="Aurelie" last="Toussaint">Aurelie Toussaint</name>
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<name sortKey="Lebrun, Nicolas" sort="Lebrun, Nicolas" uniqKey="Lebrun N" first="Nicolas" last="Lebrun">Nicolas Lebrun</name>
<name sortKey="Martin, Christelle" sort="Martin, Christelle" uniqKey="Martin C" first="Christelle" last="Martin">Christelle Martin</name>
<name sortKey="Moreno, Sarah" sort="Moreno, Sarah" uniqKey="Moreno S" first="Sarah" last="Moreno">Sarah Moreno</name>
<name sortKey="Poirier, Karine" sort="Poirier, Karine" uniqKey="Poirier K" first="Karine" last="Poirier">Karine Poirier</name>
<name sortKey="Seminatore Nole, Christine" sort="Seminatore Nole, Christine" uniqKey="Seminatore Nole C" first="Christine" last="Seminatore-Nole">Christine Seminatore-Nole</name>
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<name sortKey="Gritti, Laura" sort="Gritti, Laura" uniqKey="Gritti L" first="Laura" last="Gritti">Laura Gritti</name>
<name sortKey="Sala, Carlo" sort="Sala, Carlo" uniqKey="Sala C" first="Carlo" last="Sala">Carlo Sala</name>
</country>
<country name="Australie"><noRegion><name sortKey="Hackett, Anna" sort="Hackett, Anna" uniqKey="Hackett A" first="Anna" last="Hackett">Anna Hackett</name>
</noRegion>
<name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name>
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Novel IL1RAPL1 mutations associated with intellectual disability impair synaptogenesis

Novel IL1RAPL1 mutations associated with intellectual disability impair synaptogenesis

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