19 Jun Genetic Cause of Cushing’s Disease Detected

MedicalResearch.com Interview with:

Dr. Stratakis

Constantine A. Stratakis, MD, DMSci
Section on Endocrinology and Genetics
Eunice Kennedy Shriver National Institute of Child Health and Human Development
National Institutes of Health, Bethesda 

MedicalResearch.com: What is the background for this study?

Response: The pituitary and adrenal glands operate on a kind of feedback loop.  In response to stress, the pituitary release ACTH (Adrenocorticotropic hormone), which signals the adrenal glands to release cortisol.  Rising cortisol levels then act on the pituitary, to shut down ACTH production. In a previous study, Jacque Drouin of the Institute for Clinical Research in Montreal and colleagues had determined that the CABLES1 protein was a key player in this feedback mechanism, switching off pituitary cell division in cultures exposed to cortisol. Since this feedback mechanism appears to be impaired in many corticotropinomas, we investigated the presence of Cables1 gene mutations and copy number variations in a large group of patients with Cushing’s disease.

MedicalResearch.com: What are the main findings?

Response: Our team found that four patients had mutant mutant forms of CABLES1 that do not respond to cortisol. The mutations we identified impair the tumor suppressor function in the pituitary gland

MedicalResearch.com: What should readers take away from your report?

Response: This discovery could lead to the development of treatment strategies that simulate the function of the CABLES1 protein and prevent recurrence of pituitary tumors in people with Cushing syndrome.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Response: The next step is to decipher the biochemical pathways underlying how CABLES1 suppresses tumor formation in the pituitary gland.

MedicalResearch.com: Is there anything else you would like to add?

Response: Cushing’s is a rare disorder and so is subject to misdiagnosis.  Frequently patients present with weight gain, truncal obesity, hypertension, glucose intolerance, and infections.  If patients fail to respond to initial treatments for these symptoms, then it may be prudent to call in an endocrinologist for consultation and further evaluation 

MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.

Citation:

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

Hernández-Ramírez LC¹, Gam R², Valdés N³, Lodish M⁴, Pankratz N⁵, Balsalobre A⁶, Gauthier Y⁷, Faucz FR⁸, Trivellin G⁹, Chittiboina P¹⁰, Lane J¹¹, Kay DM¹², Dimopoulou A¹³, Gaillard S¹⁴, Neou M¹⁵, Bertherat J¹⁶, Assié G¹⁷, Villa C¹⁸, Mills JL¹⁹, Drouin J²⁰, Stratakis CA²¹.

Endocr Relat Cancer. 2017 May 22. pii: ERC-17-0131. doi: 10.1530/ERC-17-0131. [Epub ahead of print.

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Last Updated on June 19, 2017 by Marie Benz MD FAAD