- Title
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De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia
- Authors
- Gauthier, J., Champagne, N., Lafrenière, R.G., Xiong, L., Spiegelman, D., Brustein, E., Lapointe, M., Peng, H., Côté, M., Noreau, A., Hamdan, F.F., Addington, A.M., Rapoport, J.L., Delisi, L.E., Krebs, M.O., Joober, R., Fathalli, F., Mouaffak, F., Haghighi, A.P., Néri, C., Dubé, M.P., Samuels, M.E., Marineau, C., Stone, E.A., Awadalla, P., Barker, P.A., Carbonetto, S., Drapeau, P., Rouleau, G.A. and the S2D Team.
- Source
- Full text @ Proc. Natl. Acad. Sci. USA
Validation of Shank3 mutations in zebrafish. Knockdown (KD) of either of the zebrafish Shank3 genes (zs3.1, zs3.2) using selective AMOs resulted in severe morphological (A) and behavioral deficits (B) compared with wild type (WT), as illustrated using representative images taken from high-speed video films. Partial rescue was observed with coinjection of AMO and rat WT Shank3 mRNA. The pie charts depict the proportion (% of totals) of normal (control-like; yellow), severely affected (no swimming; red), and mildly affected (slow swimming; blue) embryos in each group. The results with coinjection of AMO and rat WT Shank3 or mutated (R1117X or R536W) mRNA are summarized in bar graphs (C). The asterisk denotes significant (P < 0.001) differences from the KD group. PHENOTYPE:
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Effect of Shank3 mutants on differentiation of hippocampal neurons. Transfected hippocampal neurons were identified by GFP expression (A). Overexpression of WT Shank3 in neurons leads to an increase in primary neurite outgrowth from somata (B). Overexpression of R536W (C) similarly stimulated neurite outgrowth. In contrast, expression of the R1117X truncating mutation (D) failed to do so. In E, the data are quantified in a bar histogram along with standard deviations for each bar. Neurite outgrowth significantly different from control levels (P < 0.001) is indicated with an asterisk. |