Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders.
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...
Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2012-02-01
|
Series: | PLoS Genetics |
Online Access: | http://europepmc.org/articles/PMC3276563?pdf=render |
id |
doaj-03767000fd224a4884ce09193bcfd6c7 |
---|---|
record_format |
Article |
spelling |
doaj-03767000fd224a4884ce09193bcfd6c72020-11-24T21:19:12ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042012-02-0182e100252110.1371/journal.pgen.1002521Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders.Claire S LeblondJutta HeinrichRichard DelormeChristian ProepperCatalina BetancurGuillaume HuguetMarina KonyukhPauline ChasteElodie EyMaria RastamHenrik AnckarsäterGudrun NygrenI Carina GillbergJonas MelkeRoberto ToroBeatrice RegnaultFabien FauchereauOriane MercatiNathalie LemièreDavid SkuseMartin PootRichard HoltAnthony P MonacoIrma JärveläKatri KantojärviRaija VanhalaSarah CurranDavid A CollierPatrick BoltonAndreas ChiocchettiSabine M KlauckFritz PoustkaChristine M FreitagRegina WaltesMarnie KoppEftichia DuketisElena BacchelliFiorella MinopoliLiliana RutaAgatino BattagliaLuigi MazzoneElena MaestriniAna F SequeiraBarbara OliveiraAstrid VicenteGuiomar OliveiraDalila PintoStephen W SchererDiana ZelenikaMarc DelepineMark LathropDominique BonneauVincent GuinchatFrançoise DevillardBrigitte AssoulineMarie-Christine MourenMarion LeboyerChristopher GillbergTobias M BoeckersThomas BourgeronAutism 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.http://europepmc.org/articles/PMC3276563?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Claire S Leblond Jutta Heinrich Richard Delorme Christian Proepper Catalina Betancur Guillaume Huguet Marina Konyukh Pauline Chaste Elodie Ey Maria Rastam Henrik Anckarsäter Gudrun Nygren I Carina Gillberg Jonas Melke Roberto Toro Beatrice Regnault Fabien Fauchereau Oriane Mercati Nathalie Lemière David Skuse Martin Poot Richard Holt Anthony P Monaco Irma Järvelä Katri Kantojärvi Raija Vanhala Sarah Curran David A Collier Patrick Bolton Andreas Chiocchetti Sabine M Klauck Fritz Poustka Christine M Freitag Regina Waltes Marnie Kopp Eftichia Duketis Elena Bacchelli Fiorella Minopoli Liliana Ruta Agatino Battaglia Luigi Mazzone Elena Maestrini Ana F Sequeira Barbara Oliveira Astrid Vicente Guiomar Oliveira Dalila Pinto Stephen W Scherer Diana Zelenika Marc Delepine Mark Lathrop Dominique Bonneau Vincent Guinchat Françoise Devillard Brigitte Assouline Marie-Christine Mouren Marion Leboyer Christopher Gillberg Tobias M Boeckers Thomas Bourgeron |
spellingShingle |
Claire S Leblond Jutta Heinrich Richard Delorme Christian Proepper Catalina Betancur Guillaume Huguet Marina Konyukh Pauline Chaste Elodie Ey Maria Rastam Henrik Anckarsäter Gudrun Nygren I Carina Gillberg Jonas Melke Roberto Toro Beatrice Regnault Fabien Fauchereau Oriane Mercati Nathalie Lemière David Skuse Martin Poot Richard Holt Anthony P Monaco Irma Järvelä Katri Kantojärvi Raija Vanhala Sarah Curran David A Collier Patrick Bolton Andreas Chiocchetti Sabine M Klauck Fritz Poustka Christine M Freitag Regina Waltes Marnie Kopp Eftichia Duketis Elena Bacchelli Fiorella Minopoli Liliana Ruta Agatino Battaglia Luigi Mazzone Elena Maestrini Ana F Sequeira Barbara Oliveira Astrid Vicente Guiomar Oliveira Dalila Pinto Stephen W Scherer Diana Zelenika Marc Delepine Mark Lathrop Dominique Bonneau Vincent Guinchat Françoise Devillard Brigitte Assouline Marie-Christine Mouren Marion Leboyer Christopher Gillberg Tobias M Boeckers Thomas Bourgeron Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders. PLoS Genetics |
author_facet |
Claire S Leblond Jutta Heinrich Richard Delorme Christian Proepper Catalina Betancur Guillaume Huguet Marina Konyukh Pauline Chaste Elodie Ey Maria Rastam Henrik Anckarsäter Gudrun Nygren I Carina Gillberg Jonas Melke Roberto Toro Beatrice Regnault Fabien Fauchereau Oriane Mercati Nathalie Lemière David Skuse Martin Poot Richard Holt Anthony P Monaco Irma Järvelä Katri Kantojärvi Raija Vanhala Sarah Curran David A Collier Patrick Bolton Andreas Chiocchetti Sabine M Klauck Fritz Poustka Christine M Freitag Regina Waltes Marnie Kopp Eftichia Duketis Elena Bacchelli Fiorella Minopoli Liliana Ruta Agatino Battaglia Luigi Mazzone Elena Maestrini Ana F Sequeira Barbara Oliveira Astrid Vicente Guiomar Oliveira Dalila Pinto Stephen W Scherer Diana Zelenika Marc Delepine Mark Lathrop Dominique Bonneau Vincent Guinchat Françoise Devillard Brigitte Assouline Marie-Christine Mouren Marion Leboyer Christopher Gillberg Tobias M Boeckers Thomas Bourgeron |
author_sort |
Claire S Leblond |
title |
Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders. |
title_short |
Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders. |
title_full |
Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders. |
title_fullStr |
Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders. |
title_full_unstemmed |
Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders. |
title_sort |
genetic and functional analyses of shank2 mutations suggest a multiple hit model of autism spectrum disorders. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Genetics |
issn |
1553-7390 1553-7404 |
publishDate |
2012-02-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC3276563?pdf=render |
work_keys_str_mv |
AT clairesleblond geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT juttaheinrich geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT richarddelorme geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT christianproepper geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT catalinabetancur geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT guillaumehuguet geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT marinakonyukh geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT paulinechaste geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT elodieey geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT mariarastam geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT henrikanckarsater geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT gudrunnygren geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT icarinagillberg geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT jonasmelke geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT robertotoro geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT beatriceregnault geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT fabienfauchereau geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT orianemercati geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT nathalielemiere geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT davidskuse geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT martinpoot geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT richardholt geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT anthonypmonaco geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT irmajarvela geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT katrikantojarvi geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT raijavanhala geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT sarahcurran geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT davidacollier geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT patrickbolton geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT andreaschiocchetti geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT sabinemklauck geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT fritzpoustka geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT christinemfreitag geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT reginawaltes geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT marniekopp geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT eftichiaduketis geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT elenabacchelli geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT fiorellaminopoli geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT lilianaruta geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT agatinobattaglia geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT luigimazzone geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT elenamaestrini geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT anafsequeira geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT barbaraoliveira geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT astridvicente geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT guiomaroliveira geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT dalilapinto geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT stephenwscherer geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT dianazelenika geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT marcdelepine geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT marklathrop geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT dominiquebonneau geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT vincentguinchat geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT francoisedevillard geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT brigitteassouline geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT mariechristinemouren geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT marionleboyer geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT christophergillberg geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT tobiasmboeckers geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders AT thomasbourgeron geneticandfunctionalanalysesofshank2mutationssuggestamultiplehitmodelofautismspectrumdisorders |
_version_ |
1726006530569928704 |