ArticleMolecular psychiatry2020
An autism-linked missense mutation in SHANK3 reveals the modularity of Shank3 function.
Article in Molecular psychiatry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 72 citations in OpenAlex.
- Heightened empathic responses led by imbalanced cortico-amygdala circuit inbioRxiv : the preprint server for biology · 2025Article
- A Frank Assessment of SHANK: Impacts of Pathogenic Variations in SHANK3 on Preclinical Models of Phelan McDermid Syndrome.Autism research : official journal of the International Society for Autism Research · 2025Review
- Is Shank3 a 'Friend or Foe' of the Heart? Its Role in Cardiac Calcium Homeostasis.Korean circulation journal · 2025Article
- Shank3 Overexpression Leads to Cardiac Dysfunction in Mice by Disrupting Calcium Homeostasis in Cardiomyocytes.Korean circulation journal · 2025Article
- Caskin2 is a novel talin- and Abi1-binding protein that promotes cell motility.Journal of cell science · 2024Article
- Evidence for common mechanisms of pathology between SHANK3 and other genes of Phelan-McDermid syndrome.Clinical genetics · 2024Review
- Nonsynonymous Mutations in Intellectual Disability and Autism Spectrum Disorder Gene PTCHD1 DisruptCells · 2024Article
- Article
- Critical periods and Autism Spectrum Disorders, a role for sleep.Neurobiology of sleep and circadian rhythms · 2023Article
- Autism Spectrum Disorder: Neurodevelopmental Risk Factors, Biological Mechanism, and Precision Therapy.International journal of molecular sciences · 2023Review
- Immune activation during pregnancy exacerbates ASD-related alterations in Shank3-deficient mice.Molecular autism · 2023Article
- Editorial: Identifying genetics-based mechanisms and treatments for neurodevelopmental and psychiatric disorders through data integration.Frontiers in genetics · 2023Article
- The emerging roles of Shank3 in cardiac function and dysfunction.Frontiers in cell and developmental biology · 2023Review
- Regulation of the Scar/WAVE complex in migrating cells: A summary of our understanding.Journal of biosciences · 2023Review
- The Role of Zinc and NMDA Receptors in Autism Spectrum Disorders.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Association of SHANK Family with Neuropsychiatric Disorders: An Update on Genetic and Animal Model Discoveries.Cellular and molecular neurobiology · 2022Review
- A recurrent SHANK1 mutation implicated in autism spectrum disorder causes autistic-like core behaviors in mice via downregulation of mGluR1-IP3R1-calcium signaling.Molecular psychiatry · 2022Article
- A bidirectional switch in the Shank3 phosphorylation state biases synapses toward up- or downscaling.eLife · 2022Article
- Integration of Transcriptome and Exome Genotyping Identifies Significant Variants with Autism Spectrum Disorder.Pharmaceuticals (Basel, Switzerland) · 2022Article
- Mutations affecting the N-terminal domains of SHANK3 point to different pathomechanisms in neurodevelopmental disorders.Scientific reports · 2022Article
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Authors and funding
16 authors at 3 institutions in 3 countries.
Funding
Abstract
Genome sequencing has revealed an increasing number of genetic variations that are associated with neuropsychiatric disorders. Frequently, studies limit their focus to likely gene-disrupting mutations because they are relatively easy to interpret. Missense variants, instead, have often been undervalued. However, some missense variants can be informative for developing a more profound understanding of disease pathogenesis and ultimately targeted therapies. Here we present an example of this by studying a missense variant in a well-known autism spectrum disorder (ASD) causing gene SHANK3. We analyzed Shank3's in vivo phosphorylation profile and identified S685 as one phosphorylation site where one ASD-linked variant has been reported. Detailed analysis of this variant revealed a novel function of Shank3 in recruiting Abelson interactor 1 (ABI1) and the WAVE complex to the post-synaptic density (PSD), which is critical for synapse and dendritic spine development. This function was found to be independent of Shank3's other functions such as binding to GKAP and Homer. Introduction of this human ASD mutation into mice resulted in a small subset of phenotypes seen previously in constitutive Shank3 knockout mice, including increased allogrooming, increased social dominance, and reduced pup USV. Together, these findings demonstrate the modularity of Shank3 function in vivo. This modularity further indicates that there is more than one independent pathogenic pathway downstream of Shank3 and correcting a single downstream pathway is unlikely to be sufficient for clear clinical improvement. In addition, this study illustrates the value of deep biological analysis of select missense mutations in elucidating the pathogenesis of neuropsychiatric phenotypes.
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