Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Genetic defect triggers endless recycling

15.12.2014

Benign tumors in the pituitary gland are responsible when adrenal gland cells secrete the stress hormone cortisol unchecked. An international team of scientists has now succeeded in mapping out in detail the molecular processes that lie behind this.

Patients suffering from Cushing’s syndrome are often easy to recognize: they put on considerable weight around the midriff, their faces become rounder, and their necks sturdier. In addition to these external symptoms, most sufferers also have higher blood pressure, develop muscle weakness, become diabetic, and are extremely prone to infections. In many cases, surgery is a successful treatment for Cushing’s syndrome; if it is left untreated, patients die from infections or cardiovascular problems.

Now scientists from Würzburg, Munich, and Tokyo have managed to make some progress in the search for the triggers of this disease. They have discovered at molecular level the mechanisms that are responsible for causing benign tumors of the pituitary gland to trigger Cushing’s syndrome. A leading role in this was played by the following professors: Martin Fassnacht (Würzburg University Hospital), Martin Reincke (LMU Munich University Hospital), and Masayuki Komada (Yokohama, Japan). They present their work in the current issue of the journal Nature Genetics.

Never-ending hormone secretion

A hormone is the trigger for all the symptoms of Cushing’s syndrome: cortisol – also known colloquially as cortisone. This stress hormone has important roles to play in metabolism; it is only when it is secreted in an uncontrolled manner that it throws the organism into chaos. Cortisol secretion in the adrenal gland is controlled by another hormone – adrenocorticotropin (ACTH), which is produced in the pituitary gland. If a benign tumor forms there, the gland produces ACTH unchecked, thereby raising the level of cortisol. How exactly this happens has been unclear until now.

“We have now been able to show, for the first time, that in the tumor cells of more than a third of patients there is as specific genetic mutation to an enzyme known as ubiquitin-specific protease 8,” explains Martin Fassnacht. This discovery was founded on a precise genetic characterization of benign pituitary gland tumors that produce ACTH, adds Fassnacht’s colleague and one of the lead authors of the publication, Dr. Silviu Sbiera.

Genetic defect leads to a fatal chain reaction

Ubiquitin-specific protease 8, or USP8 for short, assumes a key role when it comes to recycling proteins that are no longer needed inside cells. This also applies to the epidermal growth factor receptor: this is degraded and disposed of in the cell whenever the USP8 gene is not active. As the scientists revealed, the now discovered genetic mutations cause USP8 to remain durably activated. As a result, proteins of the epidermal growth factor receptor that are permanently no longer needed are recycled instead of disposed of as they actually should be. “In a life-threatening chain reaction, first ACTH and then cortisol are produced without restraint,” explains Fassnacht. The USP8 mutations represent a significant discovery. “They open up entirely new diagnostic and therapeutic avenues for treating Cushing’s syndrome,” adds Martin Reincke from the LMU.

The research project brought together the hormone researchers of the University of Würzburg with teams from the LMU Munich, the Helmholtz Center Munich, the Max Planck Institute of Psychiatry in Munich, and the Tokyo Institute of Technology, Yokohama (Japan). The work received support from various parties including the Federal Ministry of Education and Research, within the framework of the E-Rare program, and the University of Würzburg’s Interdisciplinary Center for Clinical Research.

Sights set on Cushing’s syndrome

In the search for the causes of Cushing’s syndrome, Würzburg endocrinologists led by Professor Martin Fassnacht and Professor Bruno Allolio, in collaboration with Dr. Davide Calebiro and Professor Martin Lohse from the Rudolf Virchow Center, have already achieved multiple successes this year. For example, they have been able to point to mutations in a gene of the adrenal gland as a frequent cause of the secretion of abnormally high levels of cortisol. They reported on the findings of this work in the New England Journal of Medicine in February. And just a few days ago they were able to publish further discoveries in the journal Nature Communications: the Würzburg researchers, under the leadership of pharmacologist Dr. Davide Calebiro, further mapped out the exact mechanisms of the mutation in the adrenal gland.

“Mutations in the deubiquitinase gene USP8 cause Cushing’s disease” Martin Reincke, Silviu Sbiera, Akira Hayakawa, Marily Theodoropoulou, Andrea Osswald, Felix Beuschlein, Thomas Meitinger, Emi Mizuno-Yamasaki, Kohei Kawaguchi, Yasushi Saeki, Keiji Tanaka, Thomas Wieland, Elisabeth Graf, Wolfgang Saeger, Cristina L Ronchi, Bruno Allolio, Michael Buchfelder, Tim M Strom, Martin Fassnacht & Masayuki Komada. Nature Genetics, doi:10.1038/ng.3166

Contact

Professor Martin Fassnacht, Department of Medicine I, Würzburg University Hospital,
T: +49 (0)931 201-39021, e-mail: fassnacht_m@ukw.de

Gunnar Bartsch | idw - Informationsdienst Wissenschaft
Further information:
http://www.uni-wuerzburg.de

More articles from Life Sciences:

nachricht Microbes can grow on nitric oxide (NO)
18.03.2019 | Max-Planck-Institut für Marine Mikrobiologie

nachricht Novel methods for analyzing neural circuits for innate behaviors in insects
15.03.2019 | Kanazawa University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Revealing the secret of the vacuum for the first time

New research group at the University of Jena combines theory and experiment to demonstrate for the first time certain physical processes in a quantum vacuum

For most people, a vacuum is an empty space. Quantum physics, on the other hand, assumes that even in this lowest-energy state, particles and antiparticles...

Im Focus: Sussex scientists one step closer to a clock that could replace GPS and Galileo

Physicists in the EPic Lab at University of Sussex make crucial development in global race to develop a portable atomic clock

Scientists in the Emergent Photonics Lab (EPic Lab) at the University of Sussex have made a breakthrough to a crucial element of an atomic clock - devices...

Im Focus: Sensing shakes

A new way to sense earthquakes could help improve early warning systems

Every year earthquakes worldwide claim hundreds or even thousands of lives. Forewarning allows people to head for safety and a matter of seconds could spell...

Im Focus: A thermo-sensor for magnetic bits

New concept for energy-efficient data processing technology

Scientists of the Department of Physics at the University of Hamburg, Germany, detected the magnetic states of atoms on a surface using only heat. The...

Im Focus: The moiré patterns of three layers change the electronic properties of graphene

Combining an atomically thin graphene and a boron nitride layer at a slightly rotated angle changes their electrical properties. Physicists at the University of Basel have now shown for the first time the combination with a third layer can result in new material properties also in a three-layer sandwich of carbon and boron nitride. This significantly increases the number of potential synthetic materials, report the researchers in the scientific journal Nano Letters.

Last year, researchers in the US caused a big stir when they showed that rotating two stacked graphene layers by a “magical” angle of 1.1 degrees turns...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

International Modelica Conference with 330 visitors from 21 countries at OTH Regensburg

11.03.2019 | Event News

Selection Completed: 580 Young Scientists from 88 Countries at the Lindau Nobel Laureate Meeting

01.03.2019 | Event News

LightMAT 2019 – 3rd International Conference on Light Materials – Science and Technology

28.02.2019 | Event News

 
Latest News

Researchers measure near-perfect performance in low-cost semiconductors

18.03.2019 | Power and Electrical Engineering

Nanocrystal 'factory' could revolutionize quantum dot manufacturing

18.03.2019 | Materials Sciences

Long-distance quantum information exchange -- success at the nanoscale

18.03.2019 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>