Woike, Daniel, Wang, Emily, Tibbe, Debora, Hassani Nia, Fatemeh, Failla, Antonio Virgilio, Kibaek, Maria, Overgard, Tinett Martesen, Larsen, Martin J, Fagerberg, Christina R, Barsukov, Igor 
ORCID: 0000-0003-4406-9803 et al (show 1 more authors)
(2022)
Mutations affecting the N-terminal domains of SHANK3 point to different pathomechanisms in neurodevelopmental disorders.
SCIENTIFIC REPORTS, 12 (1).
902-.
ISSN 2045-2322, 2045-2322
Abstract
Shank proteins are major scaffolds of the postsynaptic density of excitatory synapses. Mutations in SHANK genes are associated with autism and intellectual disability. The effects of missense mutations on Shank3 function, and therefore the pathomechanisms are unclear. Several missense mutations in SHANK3 affect the N-terminal region, consisting of the Shank/ProSAP N-terminal (SPN) domain and a set of Ankyrin (Ank) repeats. Here we identify a novel SHANK3 missense mutation (p.L270M) in the Ankyrin repeats in patients with an ADHD-like phenotype. We functionally analysed this and a series of other mutations, using biochemical and biophysical techniques. We observe two major effects: (1) a loss of binding to δ-catenin (e.g. in the p.L270M variant), and (2) interference with the intramolecular interaction between N-terminal SPN domain and the Ank repeats. This also interferes with binding to the α-subunit of the calcium-/calmodulin dependent kinase II (αCaMKII), and appears to be associated with a more severe neurodevelopmental pathology.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Humans, Nerve Tissue Proteins, Ankyrin Repeat, Protein Binding, Mutation, Missense, Child, Female, Male, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Neurodevelopmental Disorders, Protein Domains |
| Divisions: | Faculty of Health and Life Sciences |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 27 Jun 2022 09:04 |
| Last Modified: | 07 Dec 2024 22:13 |
| DOI: | 10.1038/s41598-021-04723-5 |
| Open Access URL: | https://doi.org/10.1038/s41598-021-04723-5 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3157297 |
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