ArticleMolecular psychiatry2015
Identification and functional characterization of rare SHANK2 variants in schizophrenia.
Article in Molecular psychiatry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers, 2 of them syntheses that pooled it.
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Who cites it
54 citing papers in PubMed, 2 syntheses or guidelines pooled it, 106 citations in OpenAlex.
- Disease classification for whole-blood DNA methylation: Meta-analysis, missing values imputation, and XAI.GigaScience · 2022Pooled it
- Genetic variability in scaffolding proteins and risk for schizophrenia and autism-spectrum disorders: a systematic review.Journal of psychiatry & neuroscience : JPN · 2018Pooled it
- Genome-wide tandem repeat expansions modify schizophrenia risk in the presence of a 22q11.2 deletion.Molecular psychiatry · 2026Article
- Exploring the roots of schizophrenia: Current research and future directions (Review).Experimental and therapeutic medicine · 2026Review
- Detecting suicide risk in bipolar disorder patients from lymphoblastoid cell lines genetic signatures.Translational psychiatry · 2025Article
- Pre-existing DNA methylation signatures in the prefrontal cortex of alcohol-naïve nonhuman primates define neural vulnerability for future risky ethanol consumption.Neurobiology of disease · 2025Article
- Protein-truncating variants and deletions of SHANK2 are associated with autism spectrum disorder and other neurodevelopmental concerns.Journal of neurodevelopmental disorders · 2025Article
- A Paradigmatic Case of Genetic Overlap Between Neurodevelopment Disorders and Schizophrenia Aligning with the Neurodevelopmental Continuum Hypothesis.International journal of molecular sciences · 2025Article
- AMPA Receptors in Synaptic Plasticity, Memory Function, and Brain Diseases.Cellular and molecular neurobiology · 2025Review
- Structural deficits in key domains of Shank2 lead to alterations in postsynaptic nanoclusters and to a neurodevelopmental disorder in humans.Molecular psychiatry · 2024Article
- Single-cell multi-cohort dissection of the schizophrenia transcriptome.Science (New York, N.Y.) · 2024Article
- Article
- Downregulation of the Autism Spectrum Disorder GeneJBMR plus · 2023Article
- Enhanced fear limits behavioral flexibility in Shank2-deficient mice.Molecular autism · 2022Article
- Association of SHANK Family with Neuropsychiatric Disorders: An Update on Genetic and Animal Model Discoveries.Cellular and molecular neurobiology · 2022Review
- Transcriptomic and Proteomic Analysis of CRISPR/Cas9-MediatedInternational journal of molecular sciences · 2022Article
- Transient reduction in dendritic spine density in brain-specific profilin1 mutant mice is associated with behavioral deficits.Frontiers in molecular neuroscience · 2022Article
- Brain region and gene dosage-differential transcriptomic changes inFrontiers in molecular neuroscience · 2022Article
- Imbalanced post- and extrasynaptic SHANK2A functions during development affect social behavior in SHANK2-mediated neuropsychiatric disorders.Molecular psychiatry · 2021Article
- Cellular Models in Schizophrenia Research.International journal of molecular sciences · 2021Review
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Authors and funding
13 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Recent genetic data on schizophrenia (SCZ) have suggested that proteins of the postsynaptic density of excitatory synapses have a role in its etiology. Mutations in the three SHANK genes encoding for postsynaptic scaffolding proteins have been shown to represent risk factors for autism spectrum disorders and other neurodevelopmental disorders. To address if SHANK2 variants are associated with SCZ, we sequenced SHANK2 in 481 patients and 659 unaffected individuals. We identified a significant increase in the number of rare (minor allele frequency<1%) SHANK2 missense variants in SCZ individuals (6.9%) compared with controls (3.9%, P=0.039). Four out of fifteen non-synonymous variants identified in the SCZ cohort (S610Y, R958S, P1119T and A1731S) were selected for functional analysis. Overexpression and knockdown-rescue experiments were carried out in cultured primary hippocampal neurons with a major focus on the analysis of morphological changes. Furthermore, the effect on actin polymerization in fibroblast cell lines was investigated. All four variants revealed functional impairment to various degrees, as a consequence of alterations in spine volume and clustering at synapses and an overall loss of presynaptic contacts. The A1731S variant was identified in four unrelated SCZ patients (0.83%) but not in any of the sequenced controls and public databases (P=4.6 × 10(-5)). Patients with the A1731S variant share an early prodromal phase with an insidious onset of psychiatric symptoms. A1731S overexpression strongly decreased the SHANK2-Bassoon-positive synapse number and diminished the F/G-actin ratio. Our results strongly suggest a causative role of rare SHANK2 variants in SCZ and underline the contribution of SHANK2 gene mutations in a variety of neuropsychiatric disorders.
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