The Structural, Post-Translational, and Genetic Landscape of Retinoic Acid Receptor (RAR) Pathologies

Retinoic acid receptors (RARs)—RARα, RARβ, and RARγ, encoded by RARA, RARB, and RARG—are ligand-regulated transcription factors that convert retinoid availability into cell-type-specific programs controlling development and tissue homeostasis. Disease-associated RAR alterations are usually reviewed separately as leukemia fusions, inherited developmental variants, treatment-resistance mutations, or pathway abnormalities. Here, these alteration classes are integrated within a common domain–mechanism–phenotype framework that links receptor architecture, chromatin regulation, and protein quality control to clinical presentation and therapeutic response. Attention is given to PML::RARA and variant RARA fusions in acute promyelocytic leukemia, germline RARB variants in neurodevelopmental and ocular disease, and RARG-rearranged acute myeloid leukemia. AF-1 and ligand-binding-domain variants, defective receptor turnover, and therapeutic strategies involving retinoids, arsenic trioxide, epigenetic modulation, and targeted protein degradation are also evaluated. The evidence indicates that disease phenotype and treatment response emerge from the interplay among the affected receptor domain, fusion partner, chromatin context, and capacity for protein degradation. Distinguishing established drivers from treatment-emergent lesions, biomarkers, and variants of uncertain significance is essential for accurate diagnosis and precision therapy.