Systemic and cardiac pathology induced by a clinically relevant USP8 activating mutation

Area of Science:

• Endocrinology
• Molecular Biology
• Genetics

Background:

• Cushing's disease (CD) is the most common endogenous Cushing's syndrome, driven by USP8 gene mutations.
• These mutations lead to ACTH-secreting pituitary adenomas and hypercortisolism, causing symptoms like muscle weakness and cardiovascular dysfunction.

Purpose of the Study:

• To investigate the pathogenic mechanisms of USP8 gain-of-function mutations.
• To develop and analyze a mouse model expressing a prevalent CD-associated USP8 mutation (p.S718del).

Main Methods:

• Generated a conditional transgenic mouse model expressing human USP8 (hUSP8) with the p.S718del mutation.
• Examined systemic and myocardial-specific expression of hUSP8S718del in mice.
• Assessed pituitary function, hormonal levels, and tissue-specific phenotypes.

Main Results:

• Systemic hUSP8S718del expression caused corticotroph hyperplasia but not pituitary adenomas or hypercortisolism.
• Transgenic mice exhibited muscle atrophy, bone abnormalities, cataracts, and cardiac dysfunction.
• Myocardial-specific hUSP8S718del expression replicated cardiac defects, confirming USP8's direct role in heart pathology.

Conclusions:

• USP8 gain-of-function mutations cause a syndrome with tissue-specific effects beyond pituitary tumorigenesis.
• USP8 activation directly contributes to cardiac pathology in this USP8-associated syndrome.