Cullin–RING receptors in rare disease biology

The ubiquitin-proteasome system governselective protein turnover in all eukaryotes, and its cullin-Really Interesting New Gene (RING) ligases represent the largest class of E3 ligases. Their substrate receptors (SRs) act as the 'specificity engines' of degradation, yet their contribution to human genetic disease has only recently come into focus. In this review, we provide the first systematic catalogue of 267 SRs, of which 93 are now linked to germline disorders. We synthesise emerging mechanisms, from altered degron recognition to noncanonical SR functions, and highlight how patient variants illuminate pathways for diagnosis and therapy. By connecting proteostasis, rare-disease genetics, and targeted protein degradation, SRs emerge as central nodes with broad implications for precision medicine.