USP8 Mutations Associated with Cushing's Disease Alter Protein Structure Dynamics

Area of Science:

• Endocrinology
• Molecular Biology
• Genetics

Background:

• Cushing's disease is often linked to adenomas with USP8 gene mutations.
• Mutations in exon 14 of USP8 disrupt its regulatory binding motif, leading to constitutive activation.

Purpose of the Study:

• To investigate the molecular mechanisms by which USP8 mutations cause deubiquitinase activity disruption in Cushing's disease.
• To identify and characterize novel USP8 variants in patients with Cushing's disease.

Main Methods:

• Sanger sequencing of the USP8 gene in corticotropinomas.
• Computational screening of identified USP8 variants.
• Molecular dynamics simulations to assess protein structural alterations and biological activity.

Main Results:

• Eight USP8 variants were identified, including two novel ones, within and outside the mutation hotspot.
• A novel variant, initially deemed benign, showed pathogenic patterns similar to known variants.
• All identified USP8 variants induced similar conformational changes in the USP8 protein.

Conclusions:

• USP8 mutations in Cushing's disease, regardless of specific location or annotation, induce similar pathogenic conformational changes.
• These conformational changes in USP8 likely contribute to the development of Cushing's disease.