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mRNA injections of SMN1 hypomorphic variants extend the survival of SMN-deficient zebrafish, but only partially compared with wild-type or non-pathogenic controls. (A) Median survival of smn−/− larvae injected with each of the SMN1 variants associated with SMA type II or III, was compared with both VUS and with known pathogenic and non-pathogenic SMN1 variants. Kaplan–Meier analysis was used to determine median survival. Statistical significance, compared to smn−/− mock-injected control fish (smn−/−) and wt-SMN1 mRNA-injected animals (WT), was determined by log-rank (Mantel–Cox) test. ****P < 0.0001; *P < 0.05; ns, not significant. Exact P values are also shown. Data are representative of one experiment performed three times (see Appendix Figs. S5 and S6 for additional replicates). (B) Survival curves for each of the tested SMN1 variants (solid colored line) shown relative to those for smn−/− mock-injected control fish (dotted red line) and wt-SMN1 mRNA-injected animals (dotted green line). P values are as in (A). All tested missense variants, associated with mild forms of the disease, significantly extended the survival of SMN-deficient smn−/− animals, though none matched the rescue efficiency of wt or VUS mRNA, suggesting that the presented methodology would also be useful to detect hypomorphs. These findings, combined with the data presented in Figs. 3 and 4, support that the tested 861VUS and 855VUS variants are neither pathogenic nor hypomorphic. Source data are available online for this figure.
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