Loss-of-function mutations in the CABLES1 gene are a novel cause of Cushing's disease.

摘要: The CABLES1 cell cycle regulator participates in the adrenal-pituitary negative feedback, and its expression is reduced corticotropinomas, pituitary tumors with a largely unexplained genetic basis. We investigated presence of mutations/copy number variations (CNVs) their associated clinical, histopathological molecular features patients Cushing's disease (CD). Samples from 146 pediatric (118 germline DNA only/28 tumor DNA) 35 adult (tumor CD were screened for mutations. CNVs assessed 116 (87 only/29 DNA). Four potentially pathogenic missense variants identified, two young adults (c.532G > A, p.E178K c.718C > T, p.L240F) children (c.935G > A, p.G312D c.1388A > G, p.D463G) CD; no found. four affected residues within or close to predicted cyclin-dependent kinase-3 (CDK3)-binding region protein impaired ability block growth mouse corticotropinoma line (AtT20/D16v-F2). had macroadenomas. provide evidence role as novel tumor-predisposing gene. Its function might link main mechanisms altered corticotropinomas: kinase/cyclin group regulators epidermal factor receptor signaling pathway. Further studies are needed assess prevalence mutations among other types adenomas elucidate pituitary-specific functions this