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

Laura C. Hernández-Ramírez, Ryhem Gam, Nuria Valdés, Maya B. Lodish, Nathan Pankratz, Aurelio Balsalobre, Yves Gauthier, Fabio R. Faucz, Giampaolo Trivellin, Prashant Chittiboina, John Lane, Denise M. Kay, Aggeliki Dimopoulos, Stephan Gaillard, Mario Neou, Jérôme Bertherat, Guillaume Assié, Chiara Villa, James L. Mills, Jacques DrouinConstantine A. Stratakis

Research output: Contribution to journalArticlepeer-review

67 Scopus citations


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

Original languageEnglish (US)
Pages (from-to)379-392
Number of pages14
JournalEndocrine-related cancer
Issue number8
StatePublished - Aug 2017

Bibliographical note

Funding Information:
This work was supported by the Intramural Research Program, NICHD, NIH (DIR and DIPHR, NICHD and contract HHSN275201300023I), grants from the Canadian Institutes of Health Research (R G, A N, Y G and J D) and by the Fondation Foch (Foch Hospital, Suresnes, France) (C V).

Funding Information:
We studied 146 pediatric (<18 years at diagnosis) patients with CD who are part of a large cohort evaluated at the outpatient clinic and/or admitted for clinical work-up and treatment at the National Institutes of Health (NIH) Clinical Center between 1997 and 2017 and recruited under the research protocol 97-CH-0076 (ClinicalTrials. gov: NCT00001595). The Eunice Kennedy Shriver National Institute of Child Health and Human Development Institutional Review Board approved this study, and informed assent/consent was obtained from all the patients and their parents/guardians. Clinical data were obtained directly from the patients and/or from the Clinical Research Information System. Parents and siblings of the patients were also recruited, when available.

Funding Information:
1Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA 2Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, Québec, Canada 3Service of Endocrinology and Nutrition, Hospital Universitario Central de Asturias, Instituto Universita-rio de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain 4Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota, USA 5Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, Maryland, USA 6Newborn Screening Program, Wadsworth Center, New York State Department of Health, Albany, New York, USA 7Division of Intramural Population Health Research, Epidemiology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA 8Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Paris, France 9Department of Neurosurgery, Hôpital Foch, Suresnes, France 10Service d’Endocrinologie, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris, France 11Department of Pathological Cytology and Anatomy, Hôpital Foch, Suresnes, France 12Department of Endocrinology, CHU de Liège, University of Liège, Liège, Belgium *(J L Mills, J Drouin and C A Stratakis contributed equally to this work)

Publisher Copyright:
© 2017 The authors Printed in Great Britain.


  • Corticotropinoma
  • Cushing's disease
  • Germline mutation
  • Whole-exome sequencing


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