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An autism-linked missense mutation in SHANK3 reveals the modularity of Shank3 function

Abstract

Genome sequencing has revealed an increasing number of genetic variations that are associated with neuropsychiatric disorders. Frequently, studies limit their focus to likely gene-disrupting mutations because they are relatively easy to interpret. Missense variants, instead, have often been undervalued. However, some missense variants can be informative for developing a more profound understanding of disease pathogenesis and ultimately targeted therapies. Here we present an example of this by studying a missense variant in a well-known autism spectrum disorder (ASD) causing gene SHANK3. We analyzed Shank3’s in vivo phosphorylation profile and identified S685 as one phosphorylation site where one ASD-linked variant has been reported. Detailed analysis of this variant revealed a novel function of Shank3 in recruiting Abelson interactor 1 (ABI1) and the WAVE complex to the post-synaptic density (PSD), which is critical for synapse and dendritic spine development. This function was found to be independent of Shank3’s other functions such as binding to GKAP and Homer. Introduction of this human ASD mutation into mice resulted in a small subset of phenotypes seen previously in constitutive Shank3 knockout mice, including increased allogrooming, increased social dominance, and reduced pup USV. Together, these findings demonstrate the modularity of Shank3 function in vivo. This modularity further indicates that there is more than one independent pathogenic pathway downstream of Shank3 and correcting a single downstream pathway is unlikely to be sufficient for clear clinical improvement. In addition, this study illustrates the value of deep biological analysis of select missense mutations in elucidating the pathogenesis of neuropsychiatric phenotypes.

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Acknowledgements

We are grateful to Gabriele Schuster for injection of Shank3 BAC; Yousuf O. Ali and Hui-Chen Lu for technical input on primary neuron culture; Antrix Jain and Sung Y. Jung for their help in mass spectrometry; Dinghui Yu for his help in imaging data analysis; Vicky Brandt, Aya Ito-Ishida, Callison E. Alcott, and Vincenzo A. Gennarino for editorial input. This work was supported by the Howard Hughes Medical Institute (to H.Y.Z.), a gift from Mr. Charif Souki (to the Jan and Dan Duncan Neurological Research Institute), a grant (1R01GM097207) from the National Institute of Health (to P.B.), and a supercomputer allocation (MCB120101) from XSEDE (to P.B.). The work was also supported in part by IDDRC grant number 1U54 HD083092 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development. IDDRC Neurobehavior and Neurovisualization cores were used for this project. L.W. was supported by a predoctoral fellowship from Autism Speaks (#9120). J.L.H. was supported by an NINDS K08 Award (NS091381), the Robbins Foundation, Baylor Pediatrics Pilot Award, as well as Chao Physician-Scientist Award.

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Wang, L., Pang, K., Han, K. et al. An autism-linked missense mutation in SHANK3 reveals the modularity of Shank3 function. Mol Psychiatry 25, 2534–2555 (2020). https://doi.org/10.1038/s41380-018-0324-x

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