title: Novel IL1RAPL1 mutations associated with intellectual disability impair synaptogenesis.
abstract: Mutations in interleukin-1 receptor accessory protein like 1 (IL1RAPL1) gene have been associated with non-syndromic intellectual disability (ID) 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 was 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 ID. Using immunofluorescence and electrophysiological recordings, we examined the effects of IL1RAPL1 mutant 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 because 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 ID in the patients.
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Paris 75014, France.
authors.forename: Mariana
authors.initials: M
authors.lastname: Ramos-Brossier
authors.affiliation: CNR Neuroscience Institute and Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan 20129, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Montani
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Paris 75014, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lebrun
authors.affiliation: CNR Neuroscience Institute and Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan 20129, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Gritti
authors.affiliation: IINS, CNRS UMR5297, Université de Bordeaux, Bordeaux 33000, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Martin
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Paris 75014, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Seminatore-Nole
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Laboratoire de Biochimie et Génétique Moléculaire, Hôpital Cochin, APHP, Paris 75014, France.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Toussaint
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Paris 75014, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Moreno
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Paris 75014, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Poirier
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Paris 75014, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Dorseuil
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Paris 75014, France.
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.affiliation: Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia.
authors.forename: Anna
authors.initials: A
authors.lastname: Hackett
authors.affiliation: School of Paediatrics and Reproductive Health, Robinson Institute, The University of Adelaide, Adelaide, SA 5006, Australia.
authors.forename: Jozef
authors.initials: J
authors.lastname: Gecz
authors.affiliation: Service de Génétique Médicale, Hôpital Purpan, Toulouse 31059, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Bieth
authors.affiliation: Genetics and Cytogenetics Department, GRC-UPMC, Pitié-Salpetrière CHU, Paris 75013, France and.
authors.forename: Anne
authors.initials: A
authors.lastname: Faudet
authors.affiliation: Genetics and Cytogenetics Department, GRC-UPMC, Pitié-Salpetrière CHU, Paris 75013, France and.
authors.forename: Delphine
authors.initials: D
authors.lastname: Heron
authors.affiliation: Department of Medical Genetics, Faculty of Medicine and Health Sciences, University and University Hospital Antwerp, Antwerp 2610, Belgium.
authors.forename: R
authors.initials: R
authors.lastname: Frank Kooy
authors.affiliation: Department of Medical Genetics, Faculty of Medicine and Health Sciences, University and University Hospital Antwerp, Antwerp 2610, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Loeys
authors.affiliation: IINS, CNRS UMR5297, Université de Bordeaux, Bordeaux 33000, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Humeau
authors.affiliation: CNR Neuroscience Institute and Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan 20129, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Sala
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Paris 75014, France, pierre.billuart@inserm.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Billuart
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism; D053577:Interleukin-1 Receptor Accessory Protein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D007438:Introns; D008297:Male; D009154:Mutation; D055495:Neurogenesis / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D054730:Protein Interaction Domains and Motifs; D021381:Protein Transport; D017384:Sequence Deletion; D015398:Signal Transduction; D013569:Synapses / Q000235:genetics* / Q000378:metabolism
chemical_list: C407643:IL1RAPL1 protein, human; D053577:Interleukin-1 Receptor Accessory Protein