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

Artikel i vetenskaplig tidskrift
Författare 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
Publicerad i PLoS Genetics
Volym 8
Nummer/häfte 2
Sidor e1002521
ISSN 1553-7390
Publiceringsår 2012
Publicerad vid Gillbergcentrum
Institutionen för neurovetenskap och fysiologi, sektionen för farmakologi
Sidor e1002521
Språk en
Länkar dx.doi.org/10.1371/journal.pgen.100...
https://gup.ub.gu.se/file/105571
Ämnesord 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
Ämneskategorier Barn- och ungdomspsykiatri

Sammanfattning

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.

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