Autism-associated SHANK3 missense point mutations impact conformational fluctuations and protein turnover at synapses
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Abstract
Members of the SH3- and ankyrin repeat (SHANK) protein family are considered as master scaffolds of the postsynaptic density of glutamatergic synapses. Several missense mutations within the canonical SHANK3 isoform have been proposed as causative for the development of autism spectrum disorders (ASDs). However, there is a surprising paucity of data linking missense mutation-induced changes in protein structure and dynamics to the occurrence of ASD-related synaptic phenotypes. In this proof-of-principle study, we focus on two ASD-associated point mutations, both located within the same domain of SHANK3 and demonstrate that both mutant proteins indeed show distinct changes in secondary and tertiary structure as well as higher conformational fluctuations. Local and distal structural disturbances result in altered synaptic targeting and changes of protein turnover at synaptic sites in rat primary hippocampal neurons.
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Disruption of SHANK family proteins alters PSD architecture, receptor localization, and subsequent signaling, leading to impaired synaptic transmission and plasticity that recapitulates autism-related phenotypes in animal models.
“Disruption of SHANK family proteins alters PSD architecture, receptor localization, and subsequent signaling (Bucher et al., 2021), leading to impaired synaptic transmission and plasticity that recapitulates autism-related phenotypes in animal models (Eltokhi et al., 2021; Jung and Park, 2022).”
From Biological hierarchy from genotype to phenotype in syndromic and non-syndromic autism spectrum disorder (2026) · cites this paper as Bucher et al., 2021
Bucher et al. describe SHANK3 as a PSD organizer associated with glutamate receptors (Introduction, page unavailable), and discuss how perturbed SHANK3 could change PSD protein interactions and signaling (Discussion, page unavailable). Their Results report altered localization of mutant SHANK3, but the passages do not establish altered receptor localization. The animal-model portion of the sentence is attributed to other citations, not Bucher et al. (LLM, conf=0.85)
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Ponna, S. K., Ruskamo, S., Myllykoski, M., Keller, C., Boeckers, T. M., & Kursula, P. (2018) · Journal of Neurochemistry · doi:10.1111/jnc.14322 · Cited by 25 · see citing works
Cai, Q., Hosokawa, T., Zeng, M., Hayashi, Y., & Zhang, M. (2019) · Structure · doi:10.1016/j.str.2019.11.018 · Cited by 25 · see citing works
Therapeutic approaches for shankopathies
Wang, X., Bey, A. L., Chung, L., Krystal, A. D., & Jiang, Y. (2013) · Developmental Neurobiology · doi:10.1002/dneu.22084 · Cited by 22 · see citing works
Targeting of δ-catenin to postsynaptic sites through interaction with the Shank3 N-terminus
Nia, F. H., Woike, D., Martens, V., Klüssendorf, M., Hönck, H., Harder, S., & Kreienkamp, H. (2020) · Molecular Autism · doi:10.1186/s13229-020-00385-8 · Cited by 21 · see citing works
Self-citationStructural Dynamics is a Determinant of the Functional Significance of Missense Variants
Ponzoni, L., & Bahar, İ. (2018) · Biophysical Journal · doi:10.1016/j.bpj.2017.11.1291 · Cited by 20 · see citing works
Nia, F. H., & Kreienkamp, H. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00268 · Cited by 19 · see citing works
Self-citationPonna, S. K., Myllykoski, M., Boeckers, T. M., & Kursula, P. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.06.121 · Cited by 15 · see citing works
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Autism Spectrum Disorder: Brain Areas Involved, Neurobiological Mechanisms, Diagnoses and Therapies
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Postsynaptic autism spectrum disorder genes and synaptic dysfunction
Bonsi, P., Jaco, A. D., Fasano, L., & Gubellini, P. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105564 · Cited by 67 · see citing works
Scaffold proteins as dynamic integrators of biological processes
DiRusso, C. J., Dashtiahangar, M., & Gilmore, T. D. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102628 · Cited by 55 · see citing works
Symptomatic, Genetic, and Mechanistic Overlaps between Autism and Alzheimer’s Disease
Nadeem, M. S., Hosawi, S. B. I., Alshehri, S., Ghoneim, M. M., Imam, S. S., Murtaza, B. N., & Kazmi, I. A. (2021) · Biomolecules · doi:10.3390/biom11111635 · Cited by 56 · see citing works
Chen, B., Zhao, H., Li, M., She, Q., Liu, W., Zhang, J., Zhao, W., Huang, S., & Wu, J. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-04860-3 · Cited by 21 · see citing works
Nia, F. H., Woike, D., Bento, I., Niebling, S., Tibbe, D., Schulz, K., Hirnet, D., Skiba, M., Hönck, H., Veith, K., et al. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01882-3 · Cited by 18 · see citing works
Self-citationMeta-analysis of 46,000 germline de novo mutations linked to human inherited disease
Lopes‐Marques, M., Mort, M. E., Carneiro, J., Azevedo, A., Amaro, A. P., Cooper, D. N., & Azevedo, L. (2024) · Human Genomics · doi:10.1186/s40246-024-00587-8 · Cited by 15 · see citing works
Woike, D., Wang, E., Tibbe, D., Nia, F. H., Failla, A. V., Kibæk, M., Overgård, T. M., Larsen, M. J., Fagerberg, C. R., Barsukov, I., et al. (2022) · Scientific Reports · doi:10.1038/s41598-021-04723-5 · Cited by 15 · see citing works
Self-citationRole of SHANK3 in concentrated ambient PM2. 5 exposure induced autism-like phenotype
Li, K., Liang, X., Xie, X., Tian, L., Yan, J., Lin, B., Liu, H., Lai, W., Liu, X., & Xi, Z. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e14328 · Cited by 10 · see citing works
Identification of novel drug targets and small molecule discovery for MRSA infections
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Okuzono, S., Fujii, F., Matsushita, Y., Setoyama, D., Shinmyo, Y., Taira, R., Yonemoto, K., Akamine, S., Motomura, Y., Sanefuji, M., et al. (2023) · Neuroscience Research · doi:10.1016/j.neures.2023.03.001 · Cited by 6 · see citing works
PSINDB: the postsynaptic protein–protein interaction database
Kálmán, Z. E., Dudola, D., Mészáros, B., Gáspári, Z., & Dobson, L. (2022) · Database · doi:10.1093/database/baac007 · Cited by 6 · see citing works
Woike, D., Tibbe, D., Nia, F. H., Martens, V., Wang, E. Q., Barsukov, I., & Kreienkamp, H. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03611-5 · Cited by 8 · see citing works
Self-citationStructural Insights into Protein Mutations Related to Autism Spectrum Disorders: A Systematic Review
Das, M. R., Rahman, M., & Zhou, C. (2025) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.5c00526 · Cited by 3 · see citing works
Janner, D. E., Poetini, M. R., Musachio, E. A. S., Chaves, N. S. G., Meichtry, L. B., Fernandes, E. J., Mustafa, M. M. D., de Carvalho, A. S., Gonçalves, O. H., Leimann, F. V., et al. (2024) · Comparative Biochemistry and Physiology Part C Toxicology & Pharmacology · doi:10.1016/j.cbpc.2024.109998 · Cited by 3 · see citing works
Ras, RhoA, and vascular pharmacology in neurodevelopment and aging
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Resonance assignment of the Shank1 PDZ domain
Sánta, A., Czajlik, A., Batta, G., Péterfia, B. F., & Gáspári, Z. (2022) · Biomolecular NMR Assignments · doi:10.1007/s12104-022-10069-4 · Cited by 3 · see citing works
Varella-Branco, E., Shephard, E., Toledo, V. H. C., Ramos, I. C., Lacerda, E. C. M., Carvalho, L. L. M., Fiuza, M. A., Paschalidis, M., Costa, C. I. S., Girardi, A. C. S., et al. (2026) · Molecular Psychiatry · doi:10.1038/s41380-025-03433-y · Cited by 2 · see citing works
Genetic Association of APOA5 and AKT3 Genes with Milk Production Traits in Chinese Holstein Cows
Guo, Z., Du, A., Han, B., Li, H., Tian, R., Sun, W., Zhao, G., Tian, J., Bao, X., Zhang, J., et al. (2024) · Agriculture · doi:10.3390/agriculture14060869 · Cited by 2 · see citing works
Okuzono, S., Fujii, F., Setoyama, D., Taira, R., Shinmyo, Y., Kato, H., Masuda, K., Yonemoto, K., Akamine, S., Matsushita, Y., et al. (2024) · Genes to Cells · doi:10.1111/gtc.13142 · Cited by 1 · see citing works
SHANK3–CAMSAP2 interaction links synapses to dendritic microtubule organisation in PV neuronsPreprint
Hacker, D., Lee, S., Hecht-Bucher, M., Lee, S., Lamborelle, C. S., Doil, A. N., Fanutza, T., Brueckner, A. M., Yoo, T., Ramírez‐Ríos, S., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.02.10.705051 · Cited by 2 · see citing works
Self-citationPreclinical models for autism spectrum disorder: past, present, and future
Dwivedi, S., Rajput, P., Akhtar, A., Goli, S. H., & Dusane, A. (2025) · Neuroscience · doi:10.1016/j.neuroscience.2025.10.063 · Cited by 1 · see citing works
Verma, J., Singh, R. K., Paul, S., Gupta, S., Gupta, A. K., Sharma, A. K., Kumar, M., Mehan, S., Samant, R., & Tongra, M. (2026) · Metabolic Brain Disease · doi:10.1007/s11011-026-01866-0 · Cited by 1 · see citing works
Woike, D., Tibbe, D., Nia, F. H., Martens, V., Wang, E., Barsukov, I., & Kreienkamp, H. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.04.28.538665 · Cited by 1 · see citing works
Self-citationQing, Z., Yin, Z., Chen, B., Rao, Z., Yin, D., Li, D., Lu, Y., Shi, M., Li, S., Xu, Y., et al. (2026) · Frontiers in Neuroscience · doi:10.3389/fnins.2026.1964684
“Disruption of SHANK family proteins alters PSD architecture, receptor localization, and subsequent signaling (Bucher et al., 2021), leading to impaired synaptic transmission and plasticity that recapitulates autism-related phenotypes in animal models (Eltokhi et al., 2021; Jung and Park, 2022).”
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Queiroz, L. D. F. R., Pereira, M. A. D. M., Silva, A. C. R. L. E., Menezes, G. R. S., Pereira, A. M., da Silva, M. T. M., de Negreiros, R. V., de Sousa, J. D. P., de Andrade, M. L. C., & Gonçalves, É. O. (2022) · doi:10.22533/at.ed.0752219109
ATUAÇÃO DO ENFERMERMEIRO FRENTE A PREVENÇÃO DO CÂNCER DE PRÓSTATA SOB A PERPECTIVA DA AGENDA 2030
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Synaptic dysfunctions caused by SHANK3 mutation in relation to autism-like behaviors
Jing, Y. (2024) · International Conference on Biological Engineering and Medical Science (ICBioMed) · doi:10.1117/12.3012908
Lopes‐Marques, M., Mort, M. E., Carneiro, J., Azevedo, A., Amaro, A. P., Cooper, D. N., & Azevedo, L. (2024) · Figshare · doi:10.6084/m9.figshare.26684742
Lopes‐Marques, M., Mort, M. E., Carneiro, J., Azevedo, A., Amaro, A. P., Cooper, D. N., & Azevedo, L. (2024) · Figshare · doi:10.6084/m9.figshare.25282760
Lopes‐Marques, M., Mort, M. E., Carneiro, J., Azevedo, A., Amaro, A. P., Cooper, D. N., & Azevedo, L. (2024) · Figshare · doi:10.6084/m9.figshare.26684745
Lopes‐Marques, M., Mort, M. E., Carneiro, J., Azevedo, A., Amaro, A. P., Cooper, D. N., & Azevedo, L. (2024) · Figshare · doi:10.6084/m9.figshare.25282901
Briegel, W., & Kunstmann, E. (2026) · Children · doi:10.3390/children13101297
- Authors
- Bucher, M., Niebling, S., Han, Y., Molodenskiy, D., Hassani Nia, F., Kreienkamp, H.-J., Svergun, D., Kim, E., Kostyukova, A. S., Kreutz, M. R., & Mikhaylova, M.
- Affiliations
- Humboldt-Universität zu Berlin (DE)
- European Molecular Biology Laboratory (DE)
- Leibniz Institute of Virology (LIV) (DE)
- Deutsches Elektronen-Synchrotron DESY (DE)
- Institute of Human Genetics, Center for Obstetrics and Pediatrics, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany
- University Medical Center Hamburg-Eppendorf (DE)
- Korea Advanced Institute of Science and Technology (KR)
- German Center for Neurodegenerative Diseases (DE)
- Corresponding author
- Kreutz, Michael R
- Mikhaylova, Marina
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2021-05-04
- Volume
- 10
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC8169116
- OpenAlex
- W3157356791
- Cited by
- 33
- References
- 93
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 11 · 2023: 4 · 2022: 8 · 2021: 2
- FWCI
- 3.53
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion, cc-by)
- Desy Publications Database (Deutsches Elektronen-Synchrotron DESY) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DZNE Pub (submittedVersion, other-oa)
- DESY Publication Database (PUBDB) (Deutsches Elektronen-Synchrotron)
- Funders
- Deutsche Forschungsgemeinschaft (MI1923/1-2, FOR2419 TP2, EXC-2049-390688087, FOR2419 TP3, CRC 1436 Project A02, RTG 2413 SynAge TP3 and TP4, Kr1321/9-1)
- Leibniz-Gemeinschaft (Neurotranslation)
- Deutscher Akademischer Austauschdienst (Research Stays for University Academics and Scientists Award)
- University of Hamburg (LFF-FV76)
- Bundesministerium für Bildung und Forschung (16QK10A (SAS-BSOFT))
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- SHANK3, autism spectrum disorder, missense mutations, postsynaptic density, synaptic scaffolds, protein conformational dynamics, protein turnover, synaptic targeting, glutamatergic synapses, hippocampal neurons, protein structure
- MeSH terms
- Proof of Concept Study, Animals, Autistic Disorder, Cells, Cultured, Hippocampus, Nerve Tissue Proteins, Neurons, Protein Conformation, Synapses, Point Mutation, Mutation, Missense, Mutant Proteins, Rats, Molecular Dynamics Simulation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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