Mutations in the CABLES1 gene could lead to a rare disease.
Investigators in a new study may have discovered a driving factor behind Cushing syndrome, an incurable rare disease. The condition is characterized by the production of excess cortisol, which is caused by steroid medications or tumors on the pituitary or adrenal glands.
In normal amounts, cortisol maintains blood pressure; maintains heart function; controls the immune system; raises blood sugar levels; converts fat, protein, and carbohydrates into energy; and controls bone formation, according to the National Institute of Child Health and Human Development (NICHD).
However, patients with Cushing syndrome who are exposed to excess cortisol can experience obesity, muscle weakness, fatigue, high blood pressure, high blood sugar, depression, and anxiety.
The authors of a study published by Endocrine-Related Cancer discovered that the syndrome may be caused by mutations in the CABLES1 gene.
Included in the study were 146 children with pituitary tumors examined for Cushing syndrome. The investigators assessed tumor and cell tissues from these patients, and scanned the genes of the tumors. The genes of 35 adults with Cushing syndrome and pituitary tumors were also determined.
The authors discovered that 4 patients had mutations in the CABLES1 gene that made them nonresponsive to cortisol. This finding was significant because the normal gene expresses the CABLES1 protein, which slows the proliferation of pituitary tumors that produce the adrenocorticotropin (ACTH) hormone, according to the study.
Once produced, ACTH then stimulates the adrenal gland to create cortisol. The stress hormone then causes the pituitary gland to inhibit the growth of ACTH-producing cells, which stops tumor development.
Since cortisol is not able to act on the mutated CABLES1 genes, the production of ACTH-releasing cells is not slowed or stopped.
The authors note that the genetic mutations were only discovered in a small number of patients and other genes are involved in pituitary tumor formation, according to the study. Additional studies are needed to further understand the role of CABLES1 mutations in pituitary tumor formation.
“The mutations we identified impair the tumor suppressor function in the pituitary gland,” said senior study author Constantine A. Stratakis, MD, director of the NICHD Division of Intramural Research. “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.”