Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders

Durand, Christelle; Betancur, Catalina; Boeckers, Tobias M.; Bockmann, Juergen; Chaste, Pauline; Fauchereau, Fabien; Nygren, Gudrun; Råstam, Maria; Gillberg, I. Carina; Anckarsäter, Henrik; Sponheim, Eili; Goubran‐Botros, Hany; Delorme, Richard; Chabane, Nadia; Mouren-Siméoni, Marie-Christine; Mas, P. De; Bieth, Éric; Rogé, Bernadette; Héron, Delphine; Bürglen, Lydie; Gillberg, Christopher; Leboyer, Marion; Bourgeron, Thomas

doi:10.1038/ng1933

Cited by 1,395 publications

(1,306 citation statements)

References 16 publications

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“…Furthermore, autism-linked mutations (R12C, arginine to cysteine; L68P, leucine to proline) 168,171,172 in SHANK3 impaired its integrin inhibitory function in non-neuronal cells 170 prompting a new intriguing proposal that at least some of the SHANK ASD-associated mutations alter the integrin activation in neurons.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Dendritic spine actin cytoskeleton in autism spectrum disorder

Joensuu¹,

Lanoue

Hotulainen

2018

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Section: Accepted Manuscriptmentioning

confidence: 99%

Dendritic spine actin cytoskeleton in autism spectrum disorder

Joensuu¹,

Lanoue

Hotulainen

2018

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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“…However, some exons are particularly large, so 36 amplicons were utilized to amplify the coding sequences and about 100-150 base pairs deep in the intron (see Supplementary Table S1 for primer sequences and amplicon length). In order to amplify some of these amplicons, we used the primer sequences reported by Durand et al, 14 whereas we used Primer 3 Input (http://frodo.wi.mit.edu/primer3/) to design the primers for those amplicons that we had to adapt to DHPLC parameters. We were not able to amplify exons 1 and 11, because of their high-GC content.…”

Section: Patients and Controlsmentioning

confidence: 99%

“…[11][12][13] Overall, identified genetic causes of autism can be classified as cytogenetically visible chromosomal abnormalities (B5%), copy number variants (10-20%), and single-gene disorders (B5%). 13 Molecular analyses have highlighted the role of point mutations in single genes located in some of these regions: SHANK3 (ProSAP2) on chromosome 22q13, [14][15][16][17] Neuroligin 3 (NLGN3) and Neuroligin 4 (NLGN4) on the X chromosome, 18 Neurexin 1 (NRXN1) on chromosome 2p16, [19][20][21] and Contactin Associated Protein-like 2 (CNTNAP2) on chromosome 7q35. [22][23][24] Notably, both neuroligin and neurexin proteins have key roles in the formation and functioning of synapses, particularly the alignment and activation of glutamate and GABA synapses.…”

Section: Introductionmentioning

confidence: 99%

Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders

et al. 2012

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Autism spectrum disorders (ASDs) include three main conditions: autistic disorder (AD), pervasive developmental disorder, not otherwise specified (PDD-NOS), and Asperger syndrome. It has been shown that many genes associated with ASDs are involved in the neuroligin-neurexin interaction at the glutamate synapse: NLGN3, NLGN4, NRXN1, CNTNAP2, and SHANK3. We screened this last gene in two cohorts of ASD patients (133 patients from US and 88 from Italy). We found 5/221 (2.3%) cases with pathogenic alterations: a 106 kb deletion encompassing the SHANK3 gene, two frameshift mutations leading to premature stop codons, a missense mutation (p.Pro141Ala), and a splicing mutation (c.1820-4 G4A). Additionally, in 17 patients (7.7%) we detected a c.1304 þ 48C4T transition affecting a methylated cytosine in a CpG island. This variant is reported as SNP rs76224556 and was found in both US and Italian controls, but it results significantly more frequent in our cases than in the control cohorts. The variant is also significantly more common among PDD-NOS cases than in AD cases. We also screened this gene in an independent replication cohort of 104 US patients with ASDs, in which we found a missense mutation (p.Ala1468Ser) in 1 patient (0.9%), and in 8 patients (7.7%) we detected the c.1304 þ 48C4T transition. While SHANK3 variants are present in any ASD subtype, the SNP rs76224556 appears to be significantly associated with PDD-NOS cases. This represents the first evidence of a genotype-phenotype correlation in ASDs and highlights the importance of a detailed clinical-neuropsychiatric evaluation for the effective genetic screening of ASD patients.

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“…The identification of variations in neuroligin genes ( NLGN4X and NLGN3X ) in patients with ASD suggested that proteins involved in synapse formation and synaptic transmission play an important role in the etiology of ASD (Jamain et al., 2003). Similarly, rare variations have been detected in genes coding for ion channels (e.g., CACNA1 and CACNB2 ), as well as proteins involved in synaptic structure, gene transcription, and chromatin remodeling (e.g., NRXN1 , CTTNBP2, CHD8, and SHANK3 ), indicating that altered synaptic plasticity and regulation of gene expression may also be involved in the etiology of ASD (Cross‐Disorder Group of the Psychiatric Genomics Consortium, 2013; De Rubeis et al., 2014; Durand et al., 2007). …”

Section: Introductionmentioning

confidence: 99%

Autism throughout genetics: Perusal of the implication of ion channels

et al. 2018

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BackgroundAutism spectrum disorder (ASD) comprises a group of neurodevelopmental psychiatric disorders characterized by deficits in social interactions, interpersonal communication, repetitive and stereotyped behaviors and may be associated with intellectual disabilities. The description of ASD as a synaptopathology highlights the importance of the synapse and the implication of ion channels in the etiology of these disorders.MethodsA narrative and critical review of the relevant papers from 1982 to 2017 known by the authors was conducted.ResultsGenome‐wide linkages, association studies, and genetic analyses of patients with ASD have led to the identification of several candidate genes and mutations linked to ASD. Many of the candidate genes encode for proteins involved in neuronal development and regulation of synaptic function including ion channels and actors implicated in synapse formation. The involvement of ion channels in ASD is of great interest as they represent attractive therapeutic targets. In agreement with this view, recent findings have shown that drugs modulating ion channel function are effective for the treatment of certain types of patients with ASD.ConclusionThis review describes the genetic aspects of ASD with a focus on genes encoding ion channels and highlights the therapeutic implications of ion channels in the treatment of ASD.

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Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders

Cited by 1,395 publications

References 16 publications

Dendritic spine actin cytoskeleton in autism spectrum disorder

Dendritic spine actin cytoskeleton in autism spectrum disorder

Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders

Autism throughout genetics: Perusal of the implication of ion channels

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