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.
Highlights
Shank proteins are major scaffolds of the postsynaptic density of excitatory synapses
We identified a family with several individuals affected by behavioral issues (Fig. 1a)
In the step we determined binding to δ-catenin, which we have recently identified as interaction partner of the N-terminus of Shank[321]
Summary
Shank proteins are major scaffolds of the postsynaptic density of excitatory synapses. 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. 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 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. Neurodevelopmental disorders are frequently caused by mutations in genes coding for proteins which contribute to the formation and function of synapses This has led to the term “synaptopathies”[1,2]. The mutations R12C and L68P in the SPN domain which were found in autistic patients disrupt G-protein binding[18]
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