Tiled base editing screens uncover rare second-site mutations that rescue a misfolded disease protein

A tiled adenine and cytosine base editing screen in haploid human cells identifies rare intragenic NPC1 second-site suppressor mutations, including a promiscuous corrector variant.

• Why it matters: Base editing can revert only about 30% of missense disease mutations, so additional second-site correctors are needed when the primary allele cannot be directly fixed.
• What they did: The study tiled mutagenesis across the endogenous NPC1 locus in haploid cells carrying the NPC1I1061T allele, using reporters for cholesterol transport and protein abundance to find suppressors.
• The result: Corrector mutations improved NPC1 protein stability, ER exit, lysosomal trafficking, and restored cholesterol clearance in patient-derived fibroblasts and induced neurons, enabling actionable therapeutic design.

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