Target Health Blog

Genetic Cause of Cushing Syndrome Identified

June 5, 2017


The excess cortisol found in Cushing syndrome can result from certain steroid medications or from tumors of the pituitary or adrenal glands. Symptoms of the disease include obesity, muscle weakness, fatigue, high blood pressure, high blood sugar, depression and anxiety. A new finding in a study appearing online in Endocrine-Related Cancer. (1 June 2017), suggests that mutations in the gene CABLES1 may lead to Cushing syndrome.


For the study, the authors scanned tumor and cell tissue from 146 children with pituitary tumors evaluated for Cushing syndrome at the NIH Clinical Center, as well as the genes of tumors from some of the children. Investigators in France scanned the genes of an additional 35 adult patients with Cushing syndrome and pituitary tumors. Results showed that 4 of the patients who presented with mutant forms of CABLES1, did not respond to cortisol. This is significant because, when functioning normally, the CABLES1 protein, expressed by the CABLES1 gene, slows the division and growth of pituitary cells that produce the hormone adrenocorticotropin (ACTH). In turn, ACTH stimulates the adrenal gland to produce cortisol, which then acts on the pituitary gland to halt the growth of ACTH-producing cells, effectively suppressing any tumor development. Because cortisol does not affect the four mutant forms of CABLES1, these genes leave production of ACTH-releasing cells unchecked.


According to the authors, the mutations impair the tumor suppressor function in the pituitary gland and that this discovery could lead to the development of treatment strategies that simulate the function of the CABLES1 protein, resulting in the prevention of recurrence of pituitary tumors in people with Cushing syndrome. The authors also noted that the CABLES1 mutants were found in a small proportion of patients and that other genes have been implicated in pituitary tumor formation. Additional studies are needed to fully understand how CABLES1 suppresses tumor formation in the pituitary gland.

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