SHANK3 as an autism spectrum disorder-associated gene
Abstract
SHANK3 is a synaptic scaffolding protein enriched in the postsynaptic density of excitatory synapses, and plays important roles in the formation, maturation, and maintenance of synapses. Haploinsufficiency of the SHANK3 gene causes a developmental disorder, 22q13.3 deletion syndrome (known as Phelan-McDermid syndrome), that is characterized by severe expressive language and speech delay, hypotonia, global developmental delay, and autistic behavior. Since several SHANK3 mutations have been identified in a particular phenotypic group in patients with autism spectrum disorder (ASD), the SHANK3 is strongly suspected of being involved in the pathogenesis and neuropathology of ASD. Five CpG-islands have been identified in the SHANK3 gene, and tissue-specific expression of SHANK3 is regulated by DNA methylation in an epigenetic manner. Cumulative evidence has shown that several SHANK3 variants are expressed in the developing rodent brain and that their expression is regulated by DNA methylation of intragenic promoters. We identified novel SHANK3 transcripts whose transcription started at the vicinity of the CpG-island 2 in the mouse brain. Shank3 mutant mice exhibit autistic-like behaviors, including impaired social interaction and repetitive behaviors. In this article we review recent findings in regard to higher brain functions of SHANK3, epigenetic regulation of SHANK3 expression, and SHANK3-related ASD that were obtained from genetic analyses in ASD patients, molecular biological studies using developing mouse brains, and studies of Shank3 mutant mice.
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Heterozygous mutations of the Shank3 gene are associated with up to one percent of ASD cases and are a major contributor in Phelan-McDermid syndrome.
“Heterozygous mutations of the Shank3 gene are associated with up to one percent of ASD cases 20,21 and are a major contributor in Phelan-McDermid syndrome.”
From Reduced sociability and social agency encoding in adult Shank3-mutant mice are restored through gene re-expression in real time (2021) · cites this paper as [20]
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- Authors
- Uchino, S., & Waga, C.
- Affiliations
- National Center of Neurology and Psychiatry (JP)
- Venue
- Brain and Development
- Publisher
- Elsevier BV
- Published
- 2013-02
- Volume
- 35
- Issue
- 2
- Pages
- 106-110
- ISSN
- 0387-7604 (ISSN-L)
- OpenAlex
- W1968345016
- Cited by
- 176
- References
- 29
- Citations by year
- 2026: 16 · 2025: 27 · 2024: 18 · 2023: 16 · 2022: 15 · 2021: 14 · 2020: 6 · 2019: 6 · 2018: 8 · 2017: 13 · 2016: 7 · 2015: 12 · 2014: 9 · 2013: 9
- FWCI
- 5.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain and Development (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- SHANK3, autism spectrum disorder, Phelan-McDermid syndrome, haploinsufficiency, synaptic scaffolding proteins, postsynaptic density, DNA methylation, CpG islands, epigenetic regulation, alternative transcription start sites, autism-like behavior, social interaction deficits, repetitive behavior, mouse brain development
- MeSH terms
- Animals, Child, Child Development Disorders, Pervasive, Child, Preschool, Gene Expression Regulation, Humans, Infant, Mice, Mutant Strains, Nerve Tissue Proteins, Gene Deletion, Mice, Epigenomics
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