BTBD9 encodes a BTB domain-containing protein that functions as an adaptor component of the CRL3 ubiquitin ligase complex, regulating protein degradation through polyubiquitination 1. The protein plays critical roles in sleep regulation and motor control, particularly within cerebellar circuits where it modulates Purkinje cell activity and excitability 2. BTBD9 also functions in neuroprotection by regulating the insulin/insulin-like growth factor signaling pathway through FOXO, protecting against manganese-induced oxidative stress and dopaminergic neurotoxicity 3. Genetically, BTBD9 variants are strongly associated with restless legs syndrome (RLS) across multiple populations, including Chinese, Korean, and European cohorts, with polymorphisms conferring increased disease risk 4567. Loss of BTBD9 function in animal models results in motor restlessness, sleep disruption, and altered cerebellar activity, recapitulating key RLS phenotypes 82. In cancer biology, BTBD9 functions as a tumor suppressor by promoting TNFAIP1 degradation, with its downregulation associated with increased lung cancer cell migration and poor patient survival 1. The gene's diverse functions span sleep-wake regulation, motor control, neuroprotection, and tumor suppression through distinct molecular mechanisms.