Obsah

Novel IL1RAPL1 mutations associated with intellectual disability impair synaptogenesis

Autor: R. Frank Kooy, Olivier Dorseuil, Eric Bieth, Delphine Héron, Sarah Moreno, Carlo Sala, Laura Gritti, Jozef Gecz, Anna Hackett, Caterina Montani, Christelle Martin, Anne Faudet, Aurélie Toussaint, Karine Poirier, Jamel Chelly, Bart Loeys, Yann Humeau, Pierre Billuart, Mariana Ramos-Brossier, Nicolas Lebrun, Christine Seminatore-Nole
Přispěvatelé: Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Medical Biotechnology and Translational Medicine, CNR Neuroscience Institute-University of Milan, Interdisciplinary Institute for Neuroscience, Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biochimie et génétique moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Genetics of Learning Disability Service, Hunter Genetics, School of Paediatrics and Reproductive Health, University of Adelaide-Robinson Research Institute, University of Adelaide, Service de Génétique [Purpan], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Medical Genetics, Faculty of Medicine and Health Sciences-Antwerp University Hospital [Edegem] (UZA), European Project: 241995,EC:FP7:HEALTH,FP7-HEALTH-2009-two-stage,GENCODYS(2010), European Project: ANR-10-BLAN-1434,SynIQ (synapse in cognition), European Project: ANR-10-NEUR-001,AMRePACELL, Università degli Studi di Milano = University of Milan (UNIMI)-CNR Neuroscience Institute, Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Antwerp University Hospital [Edegem] (UZA)-Faculty of Medicine and Health Sciences, Bos, Mireille, Genetic and Epigenetic Networks in Cognitive Dysfunction - GENCODYS - - EC:FP7:HEALTH2010-05-01 - 2015-04-30 - 241995 - VALID, Physiopathologie synaptique des retards mentaux chez les modèles murins - SynIQ (synapse in cognition) - ANR-10-BLAN-1434 - INCOMING, Development of new experimental models for mental retardation and autism by iPS technology: g eneration of human affected and animal model neurons by reprogramming skin fibroblasts and testing gene correction using in vitro and in vivo models - AMRePACELL - ANR-10-NEUR-001 - INCOMING
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Adult
Male
Cell signaling
Immunoprecipitation
Neurogenesis
DNA Mutational Analysis
Mutant
Synaptogenesis
[SDV.GEN] Life Sciences [q-bio]/Genetics
Biology
Polymorphism
Single Nucleotide

Article
03 medical and health sciences
0302 clinical medicine
Intellectual Disability
Genetics
Humans
Protein Interaction Domains and Motifs
[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Child
Molecular Biology
Genetics (clinical)
Sequence Deletion
030304 developmental biology
0303 health sciences
[SDV.GEN]Life Sciences [q-bio]/Genetics
Point mutation
Exons
General Medicine
Molecular biology
Introns
Cell aggregation
Pedigree
Cell biology
Transport protein
Protein Transport
Chemistry
Child
Preschool

Mutation
Synapses
Female
[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Human medicine
Interleukin-1 Receptor Accessory Protein
030217 neurology & neurosurgery
Signal Transduction
Zdroj: Human Molecular Genetics
Human Molecular Genetics, Oxford University Press (OUP), 2014, pp.523
Human Molecular Genetics, 2014, pp.523
Human molecular genetics
ISSN: 0964-6906
1460-2083
Popis: 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.
Databáze: OpenAIRE
Pro tento záznam nejsou dostupné žádné jednotky.