GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE342nnn/GSE342342/primary200OKTranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE342342GEOGSEfalseTREX1 mislocalization enables precision PROTAC therapy for a genetic diseaseProteolysis-targeting chimeras (PROTACs) have been developed primarily for cancer, and their application to genetic disease remains largely unexplored. Unlike gene editing, which requires a bespoke intervention for each patient's mutation, a protein degrader could address many mutations at once, provided they share a common, druggable feature. We asked whether protein mislocalization could serve as that feature. We tested this in retinal vasculopathy with cerebral leukoencephalopathy (RVCL), a universally fatal condition caused by gain-of-function mutations in three-prime repair exonuclease-1 (TREX1), a key negative regulator of cGAS- and STING-mediated interferon (IFN) responses. Many different mislocalized TREX1 mutants cause RVCL, producing the same multi-organ disease. Here we show that a single PROTAC eliminates all known RVCL-causing variants while sparing membrane anchored wild-type TREX1. Selectivity is associated with loss of membrane anchoring, which renders the mutant accessible to degradation, thereby preventing death in a model of RVCL while preserving the essential activity of WT TREX1. Thus, a single small molecule targets diverse mislocalized mutants, establishing altered protein localization as a druggable path for PROTAC therapy.2026/09/21GSE342342GSM9928794GSM9928793GSM9928792GSM9928791GSM9928798GSM9928797GSM9928796GSM9928795GSM9928800GSM9928789GSM9928799GSM992879034328342342Mus musculus