Cushing’s disease: A mutation with grave consequences

In an international collaboration, scientists elucidated the genetic basis of how pituitary tumors cause Cushing’s disease

December 08, 2014

Cushing’s disease is a rare condition characterized by increased secretion of the stress hormone adrenocorticotropin (ACTH) from the pituitary gland in the brain. ACTH in turn stimulates cortisol release by the adrenal glands. Thus, patients suffer from rapid weight gain and fat accumulation at the trunk, face and neck. In addition, they can develop elevated blood pressure and muscular weakness, are prone to infections and may show cognitive dysfunction or even depression. An international research team now reports that the initiating event of the dangerous cascade leading to Cushing’s disease is a gene mutation in the pituitary gland causing uncontrolled ACTH secretion.

Cushing’s disease can arise from benign tumors in glandular pituitary tissue which excessively secrete the hormone adrenocorticotropin (ACTH). Scientists from the Max Planck Institute of Psychiatry in Munich, the Ludwig-Maximilians-University Munich, the Universities of Würzburg, Erlangen and Hamburg, the Helmholtz-Center Munich and the Tokyo Institute of Technology genetically characterized benign tumors of the pituitary gland which produce ACTH. In one-third of a patient population with such pituitary tumors a mutation in the gene for ubiquitin-specific protease 8 (USP8) was specifically associated with the continuous production of ACTH. This mutation had occurred in the pituitary gland and is therefore restricted to the tumor cells.

“Our study shows a role for USP8 in the regulation of pituitary gland function. The mutations activate USP8 leading to uncontrolled recycling of the epidermal growth factor receptor, a protein that stimulates the growth of cancer cells and the production of ACTH in pituitary cells”, explains Marily Theodoropoulou, scientist at the Max-Planck-Institute of Psychiatry and shared first author of the current study. The elucidation of the genetic mechanism responsible for a lot of cases of Cushing’s disease provides a new diagnostic tool and may also lead to new treatment strategies.


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