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SHANK proteins: roles at the synapse and in autism spectrum disorder

Nature Reviews Neuroscience volume 18, pages 147–157 (2017)Cite this article

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Key Points

  • SH3 and multiple ankyrin repeat domains proteins (SHANKs) are encoded by SHANK1, SHANK2 and SHANK3 genes. The three different SHANK genes can produce multiple protein isoforms that are differentially expressed according to developmental stages, cell types and brain regions.

  • Mutations in SHANK genes are a potential monogenic cause for autism spectrum disorder.

  • Neurobiological studies in animal models indicate a wide array of functions for SHANK proteins, from synaptic scaffolding to regulating spine morphology and neurotransmission.

  • Mutant mice carrying different Shank1, Shank2 or Shank3 mutations have some distinct and shared phenotypes at the molecular and functional level. All mutants seem to have altered molecular composition of excitatory synapses and altered neurotransmission, and often display impaired social interaction and repetitive behaviour.

  • Different mutations within the same SHANKgene may cause distinct synaptic and circuitry defects and thus may be responsible for the different clinical features that are seen in patients.

  • Despite being a neurodevelopmental disorder, some neurobiological alterations in autism spectrum disorder may be reversible in adulthood.

  • Adult restoration of SHANK3 levels or restoration of downstream mediators may be a useful therapeutic approach to alleviate some of the synaptic and behavioural impairments that are associated with SHANK3 mutations.

Abstract

Several large-scale genomic studies have supported an association between cases of autism spectrum disorder and mutations in the genes SH3 and multiple ankyrin repeat domains protein 1 (SHANK1), SHANK2 and SHANK3, which encode a family of postsynaptic scaffolding proteins that are present at glutamatergic synapses in the CNS. An evaluation of human genetic data, as well as of in vitro and in vivo animal model data, may allow us to understand how disruption of SHANK scaffolding proteins affects the structure and function of neural circuits and alters behaviour.

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Figure 1: Shank genes: structure and intragenic promoters.
Figure 2: Expression patterns of Shank genes and SHANK3 isoforms.
Figure 3: SHANK-interacting proteins in the postsynaptic site.

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Acknowledgements

The authors thank N. Chen for critical comments and editing the manuscript, N. Sousa (Minho University, Portugal) and all members of the Feng laboratory for support and helpful discussion. Research related to this work in the laboratory of G.F. is supported by the Poitras Center for Affective Disorders Research at the Massachusetts Institute of Technology (MIT), Stanley Center for Psychiatric Research at Broad Institute of MIT and Harvard, National Institute of Mental Health (MH097104), Nancy Lurie Marks Family Foundation, Simons Foundation Autism Research Initiative (SFARI grant 178130) and Simons Center for the Social Brain at MIT. P.M. is supported by Society in Science, The Branco Weiss Fellowship, administered by Eidgenössische Technische Hochschule (ETH) Zürich, and European Molecular Biology Organization (EMBO) Long-Term Fellowship (ALTF 89–2016).

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Authors and Affiliations

  1. Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Massachusetts Institute of Technology (MIT), Cambridge, 02139, Massachusetts, USA

    Patricia Monteiro & Guoping Feng

  2. Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, 02142, Massachusetts, USA

    Patricia Monteiro & Guoping Feng

  3. Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, 4704–553, Portugal

    Patricia Monteiro

  4. Life and Health Sciences Research Institute (ICVS)/3B's PT Government Associate Laboratory, University of Minho, Braga/Guimarães, 4710–057, Braga, Portugal

    Patricia Monteiro

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Correspondence to Guoping Feng.

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Glossary

Intragenic promoters

Promoters located within the body of the residing gene, regulating its activity. Intragenic promoters are mainly active in tissue-specific gene expression.

Alternative splicing

A process whereby different mRNAs can be produced from a single gene through the differential incorporation of exons into the mature transcript during splicing. Frequently, various mature proteins are generated from a single gene.

Epigenetic mechanisms

A mechanism of a stable change in gene expression that does not involve changes in DNA sequence.

Concordance

The occurrence of a trait in both of two related individuals, such as twins or siblings.

Ring chromosomes

Structural aberrations of chromosomes, the long and short arms of which fuse together to form a ring. Ring chromosomes can have variable size and genetic content and are often associated with large terminal deletions.

Interstitial deletions

The loss of one or more segments of DNA within a single chromosome (intra-chromosomal deletion), thereby joining genes that were previously far apart.

Unbalanced translocations

Translocations are chromosomal abnormalities that are characterized by place exchange of parts of two or more different chromosomes. Balanced translocations have no net loss or gain of any chromosomal material, whereas unbalanced translocations have unequal exchange of chromosomal material, hence resulting in loss or gain of extra genes.

Microdeletions

Small interstitial deletions of DNA (up to 5 Mb).

Breakpoints

The specific sites of chromosomal breakage that are associated with a particular chromosomal rearrangement.

Perineuronal nets

Aggregates of extracellular matrix molecules that embed cell bodies, axon initial segments and proximal dendrites of a subset of neurons in a mesh-like structure.

Excitation/inhibition (E/I) ratio

The relationship between synaptic excitation and inhibition, two opposing forces in terms of neurotransmission.

Multisensory integration

The neural processes that are involved in synthesizing information from cross-modal stimuli.

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Monteiro, P., Feng, G. SHANK proteins: roles at the synapse and in autism spectrum disorder. Nat Rev Neurosci 18, 147–157 (2017). https://doi.org/10.1038/nrn.2016.183

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