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 CD adenomas (p.S718del). Systemic expression of hUSP8S718del 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 gain-of-function mutation in mice recapitulates key features of a USP8-associated syndrome. Our results reveal tissue-specific effects of USP8 beyond pituitary tumorigenesis and identify a direct contribution of USP8 activation to cardiac pathology.