Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Gene Mutation Discovered for Hereditary Neuroendocrine Tumor

27.07.2009
University of Utah researchers and their colleagues have identified the gene that is mutated in a hereditary form of a rare neuroendocrine tumor called paraganglioma (PGL).

The gene, called hSDH5, is required for activation of an enzyme complex that plays a critical role in the chemical reactions that take place within cells to convert biochemical energy into usable energy. This study will be published in the journal Science, to be released online in Science Express on July 23, 2009.

Paragangliomas are rare, generally benign tumors that arise from cells called glomus cells, which are located along blood vessels and play a role in regulating blood pressure and blood flow. Approximately 25 percent of paragangliomas are hereditary. Of the four familial PGL syndromes, three forms have previously been associated with mutations in genes of the succinate dehydrogenase (SDH) complex, an enzyme complex involved in the ability of cells to extract energy from nutrients.

Studies in Yeast

“Defects in mitochondria, the power sources of the cell, have been implicated in a variety of human disorders, including cancer,” says Jared Rutter, PhD, associate professor of biochemistry at the University of Utah School of Medicine, investigator at the University’s Huntsman Cancer Institute, and lead author of the study. “Because it is incredibly difficult to perform in-depth studies in humans, we decided to use a much simpler model system, the yeast Saccharomyces cerevisiae, in order to study mitochondrial functions before going back to humans and determining whether what we learned in yeast was also relevant to humans. Following this strategy, we first characterized a mitochondrial protein called Sdh5 in yeast and then moved on to study its potential role in human disease.”

Sdh5 is a mitochondrial protein that is highly conserved, meaning that it has remained largely unchanged throughout the course of evolution and likely performs similar essential cellular functions in both yeast and humans. Rutter and his colleagues discovered that, in yeast, the Sdh5 protein is needed for the SDH complex to function normally. They also found that Sdh5 is required for activation of another protein called Sdh1 that is also part of the SDH complex.

Studies in Humans

“The amino acid sequence of yeast Sdh5 is 44 percent identical to its human counterpart, which we’ve named hSDH5. This gave us some confidence that the Sdh5 functions we discovered in yeast would also be carried out by human hSdh5,” explains Rutter. “Previous genetic studies have shown that the hereditary paragangliomas PGL1, PGL3, and PGL4 are associated with mutations causing loss of SDH activity. Although the gene for PGL2 had not been identified, we knew that it was located on the same chromosome as the hSDH5 gene.”

Rutter and his colleagues sequenced the hSDH5 gene in three individuals with PGL2 from a previously described Dutch lineage. They identified a single DNA nucleotide change which resulted in a mutation in the most conserved region of the protein. Of the 45 individuals within the affected lineage who inherited the mutation, 33 have developed PGL2, providing strong evidence that hSDH5 is the PGL2 gene. The seven individuals who inherited the mutation from their mothers are unaffected, suggesting an inheritance pattern that is specific to the parent of origin.

The researchers also discovered that, as in yeast, the inactivation of hSDH5 dramatically impaired the activity of the SDH complex, which was decreased by approximately 95% in tumors from three patients with PGL2.

Implications on Genetic Testing

The identification of hSDH5 as the PGL2 gene has potential clinical implications for patients with familial PGL syndromes. Genetic testing is suggested for the management of PGL, even when it does not seem to be inherited, in order to identify individuals who are at risk for developing tumors.

“Individuals with familial PGLs tend to be affected at a younger age with tumors at multiple sites,” says Rutter. “Including hSDH5 in DNA screening will allow for more comprehensive genetic testing, as well as earlier detection and treatment.”

Huaixiang Hao, a graduate student in Rutter’s laboratory, conducted the majority of the experiments in this study. Other study contributors include Oleh Khalimonchuk, Ph.D. and Dennis Winge, Ph.D. in the department of medicine at the University of Utah and Joshua Schiffman, M.D. and Brandon Bentz, M.D. from Huntsman Cancer Institute. Noah Dephoure, Ph.D. and Steven Gygi, Ph.D. from Harvard Medical School, as well as a number of Dutch scientists, were also involved in the study.

Jared Rutter | Newswise Science News
Further information:
http://www.utah.edu

More articles from Life Sciences:

nachricht A novel socio-ecological approach helps identifying suitable wolf habitats
17.02.2017 | Universität Zürich

nachricht New, ultra-flexible probes form reliable, scar-free integration with the brain
16.02.2017 | University of Texas at Austin

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Switched-on DNA

20.02.2017 | Materials Sciences

Second cause of hidden hearing loss identified

20.02.2017 | Health and Medicine

Prospect for more effective treatment of nerve pain

20.02.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>