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USP8 – Cushing Disease due to Pituitary Adenoma

Cushing disease due to pituitary adenoma is caused by ACTH-secreting corticotroph tumors. Genetic studies have identified somatic mutations in the ubiquitin-specific protease 8 (USP8) gene as a major driver in these tumors.

Somatic gain-of-function mutations cluster within the 14-3-3 binding motif in exon 14 of USP8, most frequently p.Ser718Pro, p.Ser719del, and p.Pro720Arg. These variants occur in 62% of ACTH-secreting pituitary adenomas (67/108) (PMID:25675982) and in 36% of a larger multicenter series (48/134) (PMID:25942478), with similar prevalence in pediatric cohorts (31%, 13/42) (PMID:28505279).

Mutant USP8 proteins disrupt the USP8–14-3-3 interaction, enhance deubiquitinase activity toward EGFR, prolong EGFR signaling, upregulate POMC transcription, and increase ACTH secretion. In vitro knockdown of USP8 or EGFR inhibition attenuates ACTH release, confirming a gain-of-function mechanism (PMID:25675982; PMID:26578638).

Clinically, USP8-mutated tumors are more common in females, present as microadenomas with higher rates of surgical remission but increased recurrence risk. Notably, the p.Pro720Arg variant predicts favorable responsiveness to pasireotide, highlighting its potential as a predictive biomarker.

Integration of USP8 mutation testing into clinical practice can improve diagnostic accuracy, guide therapeutic decisions including EGFR or SS receptor–targeted therapies, and stratify patients by recurrence risk. Key take-home: USP8 somatic mutations are a strong, actionable driver in Cushing disease due to pituitary adenoma.

References

  • Cell research • 2015 • Recurrent gain-of-function USP8 mutations in Cushing's disease. PMID:25675982
  • The Journal of clinical endocrinology and metabolism • 2015 • The Gene of the Ubiquitin-Specific Protease 8 Is Frequently Mutated in Adenomas Causing Cushing's Disease. PMID:25942478
  • European journal of endocrinology • 2016 • The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease. PMID:26578638
  • The Journal of clinical endocrinology and metabolism • 2017 • Somatic USP8 Gene Mutations Are a Common Cause of Pediatric Cushing Disease. PMID:28505279

Evidence Based Scoring (AI generated)

Gene–Disease Association

Strong

Recurrent somatic USP8 variants identified in 36-62% of corticotroph adenomas across multiple cohorts ([PMID:25675982]; [PMID:25942478]; [PMID:28505279]); concordant functional data.

Genetic Evidence

Strong

Somatic gain-of-function mutations in exon 14 detected in 67/108 ACTH-secreting pituitary adenomas ([PMID:25675982]) and 48/134 patients ([PMID:25942478]); reached genetic evidence cap.

Functional Evidence

Moderate

Functional assays show disruption of 14-3-3 binding, increased EGFR stability, enhanced POMC transcription and ACTH secretion; phenotype rescue upon USP8 or EGFR inhibition ([PMID:25675982]; [PMID:26578638]).