New NIH study reveals mutations in gene CABLES1 may lead to Cushing syndrome


A new study conducted by researchers at the National Institutes of Health (NIH) shows that mutations in the gene CABLES1 may lead to Cushing syndrome, a rare disorder that makes the human body produce excess stress hormone cortisol.

The cortisol found in Cushing syndrome can be generated from certain steroid medications or from tumours of the pituitary or adrenal glands.

Patients suffering from the disease may have certain symptoms such as obesity, muscle weakness, fatigue, high blood pressure, high blood sugar, depression and anxiety.

Along with researchers at other institutions in the US, France and Canada, the research team at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) has scanned tumour and cell tissue from 146 children with pituitary tumours assessed for Cushing syndrome at the NIH Clinical Centre.

The NIH researchers also scanned the genes of tumours from some of the children, while the researchers from France examined the genes of an additional 35 adult patients with Cushing syndrome and pituitary tumours.

The study revealed that four of the patients have mutant forms of CABLES1 that do not respond to cortisol.

When functioning normally, the CABLES1 protein, expressed by the CABLES1 gene, slows the division and growth of pituitary cells that generate the hormone adrenocorticotropin (ACTH).

ACTH, in turn, stimulates the adrenal gland to produce cortisol that works on the pituitary gland to stop the growth of ACTH-producing cells, effectively suppressing any tumour development.

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

The genes leave the production of ACTH-releasing cells unchecked as cortisol does not affect the four mutant forms of CABLES1 discovered by the researchers.

NICHD intramural research division director Dr Constantine Stratakis said: “The mutations we identified impair the tumour 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 tumours in people with Cushing syndrome.”

The research shows that the CABLES1 mutants were found in a small proportion of patients and other genes have been implicated in pituitary tumour formation.


Image: Pituitary gland. Photo: courtesy of National Institutes of Health.