Patients with Cushing’s syndrome suffer from increased body weight and body fat accumulation at the trunk, the face (‘moon face’), and the back (‘buffalo hump). In addition, they can develop elevated blood pressure, depression, infections and myopathy. A central role in the etiology of Cushing’s syndrome plays the stress hormone adrenocorticotropin, which is produced by the pituitary gland in response to stressful events. Adrenocorticotropin is stimulating cortisol release by the adrenal gland. An international research team reports that the initiating event of the dangerous cascade leading to Cushing’s syndrome is a gene mutation in the pituitary causing uncontrolled adrenocorticotropin secretion.
The discovery emerged from the genetic characterization of benign tumors of the pituitary gland which produces ACTH in excess amounts. The team, which included researchers from Germany and Japan and was led by Professor Martin Reincke of the LMU Medical Center, were able to show that in one-third of a patient population with such pituitary tumors, a mutation in the gene for the protein USP8 (ubiquitin-specific protease 8) was specifically associated with the continuous production of adrenocorticotropin. This mutation had occurred in the pituitary gland and is therefore restricted to the tumor cells.
“The gene for USP8 plays a role in the regulation of pituitary gland function. It re-cycles a key protein, epidermal growth factor receptor, from the cellular sink. The newly identified mutations activate USP8 irreversibly leading to uncontrolled recycling of epidermal growth factor receptor and unrestrained production of adrenocorticotropin,” says Martin Reincke. In collaboration with a group at the Helmholtz Zentrum München, the Max Planck Institut for Psychiatry München and the Tokyo Institute of Technology, Yokohama, Japan, the group showed in detail the mechanisms how USP8 mutations cause this severe disease.
The elucidation of the genetic mechanism responsible for a significant fraction of cases of Cushing’s disease provides a new diagnostic tool, and may also lead to new approaches to treatment. To enable further investigations towards this end, the German Cushing Register, which is maintained by Professor Martin Reincke at the LMU Medical Center, has received a grant of 400,000 Euro from the Else Kröner-Fresenius Foundation. A recently initiated European research consortium devoted to the study of Cushing’s syndrome, of which Professors Beuschlein and Fassnacht are members is supported by a grant of 700,000 Euro from the ERA-NET program administered by the Federal Ministry for Education and Research.
Reincke, M. et al. (2014). Mutations in deubiquitinase USP8 cause Cushing’s disease, Nature Genetics, doi: 10.1038/ng.3166
Helmholtz Zentrum München, as German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches for the diagnosis, treatment and prevention of major widespread diseases such as diabetes mellitus and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The head office of the Center is located in Neuherberg in the north of Munich. Helmholtz Zentrum München has a staff of about 2,200 people and is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 34,000 staff members.
Munich University Hospital (LMU) treats around 500,000 outpatients, inpatients and semi-residential patients each year at its Großhadern and City Centre Campuses. Just over 2,000 beds are available to its 29 specialist clinics, eleven institutes and five departments, and its 45 interdisciplinary centres. Of a total of 9,450 employees, around 1,600 are doctors and 3,200 are nursing staff. Munich University Hospital has been a public-law institution since 2006. Together with the Medical Faculty of Ludwig Maximilians University, Munich University Hospital is involved in four special research areas of the German Research Foundation (SFB 684, 914, 1054, 1123), three Transregios (TRR 127, 128, 152) belonging to Clinical Research Group 809, and two Graduate Colleges belonging to the German Research Foundation (GK 1091, 1202). This is in addition to the Center for Integrated Protein Sciences (CIPSM), Munich Center of Advanced Photonics (MAP), Nanosystems Initiative Munich (NIM) and Munich Cluster for Systems Neurology (SyNergy) – all institutes of excellence – and the Graduate School of Systemic Neurosciences (GSN-LMU), the Graduate School of Quantitative Biosciences Munich (QBM) and the Graduate School Life Science Munich (LSM).
Scientific contact at Munich University Hospital:
Prof. Dr. med. Martin Reincke, Direktor Medizinische Klinik und Poliklinik IVKlinikum der Universität München (LMU), Campus Innenstadt, Ziemssenstraße 1, 80336 München – Phone: +49-(0)89-440052100 – Fax.: +49-(0)89-440054428
Scientific contact at Helmholtz Zentrum München:
Dr. Tim Strom, Helmholtz Zentrum München – German Research Center for Environmental Health (GmbH), Institute of Human Genetics, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany – Phone: +49(0)89-3187-3297 – Email