RLIM (ring finger protein, LIM domain interacting) is an X-linked E3 ubiquitin ligase that functions as a negative coregulator of transcription through multiple mechanisms. Primarily, RLIM mediates ubiquitination and degradation of LIM cofactors LDB1 and LDB2, allowing DNA-bound LIM homeodomain transcription factors to interact with alternative partners 12. RLIM additionally regulates telomere-mediated growth suppression by targeting TERF1 for degradation and activates random X-chromosome X by degrading ZFP42/REX1 [UniProt]. During neural development, RLIM stabilizes ZC4H2, which in turn stabilizes RNF220 to facilitate Sonic hedgehog signaling in cerebellar granule neuron progenitors and medulloblastoma progression 3. Mutations in RLIM cause Tonne-Kalscheuer syndrome, an X-linked recessive disorder characterized by intellectual disability, developmental delay, and congenital abnormalities in hemizygous males 4. RLIM was identified as a novel X-linked intellectual disability gene through X-exome screening 5, and gene duplications at Xq13.2-q13.3 including RLIM produce mild neurocognitive phenotypes with increased RLIM expression reducing MDM2 levels 6. Additionally, pathogenic RLIM missense variants associate with reduced human lifespan through cancer-related pathways 7.