Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders.

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Leblond, Claire S (author)

Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders.

Article/chapterEnglish2012

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2012-02-09
Public Library of Science (PLoS),2012
electronicrdacarrier

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LIBRIS-ID:oai:gup.ub.gu.se/155521
https://gup.ub.gu.se/publication/155521URI
https://doi.org/10.1371/journal.pgen.1002521DOI
https://lup.lub.lu.se/record/2384371URI

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Language:English

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SwePubSwePub

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Subject category:ref swepub-contenttype
Subject category:art swepub-publicationtype

Notes

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.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Psykiatri hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Psychiatry hsv//eng
Adaptor Proteins
Signal Transducing
Genetics
Metabolism
Adult
Alternative Splicing
Genetics
Cell Line
Child
Child Development Disorders
Pervasive
Genetics
Child
Preschool
Female
Gene Dosage
Genetics
Gene Expression Regulation
Humans
Male
Nerve Tissue Proteins
Genetics
Neurons
Cytology
Protein Isoforms
Genetics
Metabolism
RNA Splice Sites
Genetics
Receptors
Nicotinic
Genetics
Metabolism
Sequence Deletion
Genetics
Synapses
Genetics
Pathology
Tissue Distribution

Added entries (persons, corporate bodies, meetings, titles ...)

Heinrich, Jutta (author)
Delorme, Richard (author)
Proepper, Christian (author)
Betancur, Catalina (author)
Huguet, Guillaume (author)
Konyukh, Marina (author)
Chaste, Pauline (author)
Ey, Elodie (author)
Råstam, MariaLund University,Lunds universitet,Barn- och ungdomspsykiatri,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Child and Adolescent Psychiatry,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine(Swepub:lu)med-mr_ (author)
Anckarsäter, Henrik,1966Lund University,Lunds universitet,Rättspsykiatri, Malmö,Forskargrupper vid Lunds universitet,Forensic Psychiatry, Malmö,Lund University Research Groups(Swepub:lu)med-hka (author)
Nygren, Gudrun,1957Gothenburg University,Göteborgs universitet,Gillbergcentrum,Gillberg Neuropsychiatry Centre(Swepub:gu)xnygrg (author)
Gillberg, I Carina,1949Gothenburg University,Göteborgs universitet,Gillbergcentrum,Gillberg Neuropsychiatry Centre(Swepub:gu)xgillc (author)
Melke, Jonas,1971Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för farmakologi,Institute of Neuroscience and Physiology, Department of Pharmacology(Swepub:gu)xmelkj (author)
Toro, Roberto (author)
Regnault, Beatrice (author)
Fauchereau, Fabien (author)
Mercati, Oriane (author)
Lemière, Nathalie (author)
Skuse, David (author)
Poot, Martin (author)
Holt, Richard (author)
Monaco, Anthony P (author)
Järvelä, Irma (author)
Kantojärvi, Katri (author)
Vanhala, Raija (author)
Curran, Sarah (author)
Collier, David A (author)
Bolton, Patrick (author)
Chiocchetti, Andreas (author)
Klauck, Sabine M (author)
Poustka, Fritz (author)
Freitag, Christine M (author)
Waltes, Regina (author)
Kopp, Marnie (author)
Duketis, Eftichia (author)
Bacchelli, Elena (author)
Minopoli, Fiorella (author)
Ruta, Liliana (author)
Battaglia, Agatino (author)
Mazzone, Luigi (author)
Maestrini, Elena (author)
Sequeira, Ana F (author)
Oliveira, Barbara (author)
Vicente, Astrid (author)
Oliveira, Guiomar (author)
Pinto, Dalila (author)
Scherer, Stephen W (author)
Zelenika, Diana (author)
Delepine, Marc (author)
Lathrop, Mark (author)
Bonneau, Dominique (author)
Guinchat, Vincent (author)
Devillard, Françoise (author)
Assouline, Brigitte (author)
Mouren, Marie-Christine (author)
Leboyer, Marion (author)
Gillberg, Christopher,1950Gothenburg University,Göteborgs universitet,Gillbergcentrum,Gillberg Neuropsychiatry Centre(Swepub:gu)xgilch (author)
Boeckers, Tobias M (author)
Bourgeron, Thomas (author)
Barn- och ungdomspsykiatriSektion IV (creator_code:org_t)

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In:PLoS Genetics: Public Library of Science (PLoS)8:21553-73901553-7404

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By the author/editor: Leblond, Claire ...; Heinrich, Jutta; Delorme, Richard; Proepper, Christ ...; Betancur, Catali ...; Huguet, Guillaum ...; show more...; Konyukh, Marina; Chaste, Pauline; Ey, Elodie; Råstam, Maria; Anckarsäter, Hen ...; Nygren, Gudrun, ...; Gillberg, I Cari ...; Melke, Jonas, 19 ...; Toro, Roberto; Regnault, Beatri ...; Fauchereau, Fabi ...; Mercati, Oriane; Lemière, Nathali ...; Skuse, David; Poot, Martin; Holt, Richard; Monaco, Anthony ...; Järvelä, Irma; Kantojärvi, Katr ...; Vanhala, Raija; Curran, Sarah; Collier, David A; Bolton, Patrick; Chiocchetti, And ...; Klauck, Sabine M; Poustka, Fritz; Freitag, Christi ...; Waltes, Regina; Kopp, Marnie; Duketis, Eftichi ...; Bacchelli, Elena; Minopoli, Fiorel ...; Ruta, Liliana; Battaglia, Agati ...; Mazzone, Luigi; Maestrini, Elena; Sequeira, Ana F; Oliveira, Barbar ...; Vicente, Astrid; Oliveira, Guioma ...; Pinto, Dalila; Scherer, Stephen ...; Zelenika, Diana; Delepine, Marc; Lathrop, Mark; Bonneau, Dominiq ...; Guinchat, Vincen ...; Devillard, Franç ...; Assouline, Brigi ...; Mouren, Marie-Ch ...; Leboyer, Marion; Gillberg, Christ ...; Boeckers, Tobias ...; Bourgeron, Thoma ...; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Psychiatry

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By the university: University of Gothenburg; Lund University

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