Génétique de la maladie de Cushing

Abstract

Cushing's disease is caused by corticotroph adenomas of the pituitary. To explore molecular mechanisms of endocrine autonomy, we recently performed exome sequencing of 10 corticotroph adenomas [1] identifying somatic mutations in the USP8 deubiquitinase gene in 4 of 10 adenomas. The mutations clustered in the 14-3-3 protein-binding motif enhancing proteolytic cleavage and catalytic activity of USP8. Cleaved USP8 led to increased EGF receptor deubiquitination impairing its downregulation and sustaining EGF signaling. USP8 mutants enhanced promoter activity of the gene for proopiomelanocortin. Our data show that dominant mutations in USP8 cause Cushing's disease via activation of EGF receptor signaling. In a follow-up study, we performed a retrospective, multicentric, genetic analysis of 134 functioning and 11 silent corticotroph pituitary adenomas using Sanger sequencing. Clinical data from these patients have been collected and examined within the context of the mutational status of USP8. New mutations were characterized by functional studies. Somatic mutations in USP8 were found in 48 (36%) adenomas from patients with Cushing's disease, but in none of the 11 silent corticotropinomas. The prevalence was higher in adults than in pediatric cases and in females than in males. Adults having USP8-mutated adenomas were diagnosed at an earlier age (36 vs. 44 years) than those with wild-type adenomas. Future research will be directed towards therapeutic targeting of USP8 in corticotroph adenomas.