Dis Model Mech

Cushing's disease (CD), the most common endogenous Cushing's syndrome, is caused by activating mutations in the ubiquitin-specific protease 8 (USP8) gene. These mutations drive adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas and hypercortisolism. Clinical manifestations include muscle weakness, osteopenia, cataracts and cardiovascular dysfunction. To investigate the pathogenic mechanisms of USP8 gain of function, we generated a conditional transgenic mouse model expressing human USP8 (referred to as hUSP8) carrying the most prevalent activating mutation in mice induced diffuse corticotroph hyperplasia of ACTH+ cells, rather than pituitary microadenomas, and did not lead to hypercortisolemia. Despite preservation of the hypothalamic-pituitary-adrenal axis, transgenic mice developed skeletal muscle atrophy, bone abnormalities, corneal keratitis with cataracts and cardiac dysfunction. Notably, myocardial-specific expression of hUSP8S718del recapitulated cardiac defects seen in mice with ubiquitous expression, demonstrating the direct role of USP8 activation in the heart. These findings show that expression of a clinically relevant USP8 gainof-function mutation in mice recapitulates key features of a USP8associated syndrome. Our results reveal tissue-specific effects of USP8 beyond pituitary tumorigenesis and identify a direct contribution of USP8 activation to cardiac pathology.