RLIM-associated neurodevelopmental disorders: From clinical spectrum to molecular mechanisms

The E3 ubiquitin ligase RLIM (also known as RNF12) plays a central role in ubiquitin-dependent signaling pathways that regulate mammalian development. Missense variants in the RLIM gene cause Tønne-Kalscheuer syndrome (TOKAS), an X-linked recessive neurodevelopmental disorder affecting males, characterized by intellectual disability, developmental delay, and congenital abnormalities affecting the craniofacial, urogenital, ocular, and skeletal systems, as well as congenital diaphragmatic hernia. Additionally, RLIM duplications lead to a similar neurodevelopmental disorder, Chromosome Xq13 duplication syndrome. That both loss and gain of RLIM function produce overlapping neurodevelopmental phenotypes highlights the dosage sensitivity of this E3 ligase and points to its tightly regulated roles in human development. Despite an increasing number of reported cases, RLIM-associated disorders remain underdiagnosed and poorly understood, with no cure or targeted treatments, largely due to limited insight into the cellular and molecular mechanisms underlying their pathogenesis. Here, we review current knowledge of RLIM biology across molecular, cellular, and genetic levels. We summarize the genetic basis, diagnostic criteria, and clinical spectrum of RLIM-associated disorders and integrate this with current understanding of RLIM-dependent ubiquitin signaling. By bringing together insights from biochemistry, cell signaling, and genetics, this review aimed to serve as a mechanistically informed reference for researchers and clinicians working on RLIM variants. We rank candidate RLIM substrates by the strength of the evidence linking them to disease. Finally, we discuss the key open questions that must be addressed to achieve a comprehensive cellular and molecular understanding of RLIM-associated disorders and thus lay the foundation for future therapeutic interventions.