SARM1

Cilia effects upon perturbation of SARM1

Cilia number / % ciliated:

Decreased cilia number

Loss-of-function effect:

Shorter cilia

Overexpression effect:

Decreased

Ciliogenesis screen results (4 screens)

• Wheway et al. 2015 (siRNA) [siRNA]: Ciliogenesis Defect (z=-3.16) PMID:26167766
• Breslow et al. 2018 (CRISPR) [CRISPR]: No Significant Effect PMID:29459680
• Roosing et al. 2015 (siRNA) [siRNA]: No effect PMID:26595381
• Elliott et al. 2025 (CRISPRa) [CRISPRa]: Disassembly Trigger (casTLE Effect=-6.45) PMID:41160700

Subcellular localization

cilia associated gene

Functional category

• Ciliary assembly/disassembly
• Actin & cytoskeleton regulation
• Signaling (Hedgehog, GPCRs, ion channels)

Function

Sarm1 inhibition restores cilia in cells with FCD-associated mutations, raising the prospect of a potential therapeutic strategy. Specifically, because FMCD disorders commonly arise from somatic gain-of-function mutations (70–73), we asked whether FMCD-associated mutations promote cilia loss in a manner similar to that seen upon CRISPRa-based overexpression of disassembly mediators. We first evaluated a SARM1 variant producing a G528S mutation that was identified in an FCD-I case (70). We established Tet-Sarm1-Flag NIH-3T3 cell lines that inducibly overexpress wild-type SARM1, SARM1-G528S, or SARM1-V331E, a mutant previously shown to increase SARM1 activity (74, 75). For these transgenes, brief Dox-inducible expression led to significantly reduced ciliation (Fig. 5B). Notably, under these conditions, the G528S and V331E SARM1 mutants both caused a significantly greater loss of cilia than wild-type SARM1 (Fig. 5B) despite comparable or mildly reduced levels of expression (fig. S6A). These effects were fully reversed by DSRM-3716, confirming that SARM1-G528S reduces ciliation via its NADase activity. Thus, cilia loss is potentiated by a SARM1-G528S variant, and this effect is phenocopied by an established hyperactive SARM1 mutant.