It has been demonstrated that the hotspot mutations S427F/Y in RXRα induce the activation of the PPRAγ/RXRα pathway in bladder cancer, leading to suppression of cytokine secretion from cancer cells.8 The crystal structure of the PPARγ/RXRαS427F bound to 9-cis RA (PDB ID 5JI0)1 suggests that the mutation does not affect the organization of the residues around the site of the mutation, but the aromatic interaction between RXRα S427F and the terminal tyrosine Tyr477 found in all PPARs is responsible for the activation of PPARγ and stabilization of the heterodimer.7,8. The gene discussed is RXRA; the disease is cancer.