Potential Genetic Cause of Cushing Syndrome Found

A recent study suggests that mutations in the gene Cdk5 And Abl Enzyme Substrate 1 (CABLES1) may lead to Cushing syndrome, a rare disorder in which the body overproduces the stress hormone cortisol.

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 large team of scientists led by those at the National Institute of Child Health and Human Development (Bethesda, MD, USA) in collaboration with other institutions in the USA, France and Canada, scanned tumor and cell tissue from 146 children with pituitary tumors evaluated for Cushing syndrome. They also scanned 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.

The team identified four of the patients who have mutant forms of CABLES1 that do not respond to cortisol and these four patients had macroadenomas. 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 discovered by the scientists, these genes leave production of ACTH-releasing cells unchecked.

Constantine A. Stratakis, MD, the lead investigator and senior author of the study said, “The mutations we identified impair the tumor suppressor function in the pituitary gland. 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.” The study was published on May 22, 2017, in the journal Endocrine-Related Cancer.

Related Links:
National Institute of Child Health and Human Development