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 reports about: > Cancer > DNA > DNA screening > Dutch landscape > Genetic clues > Mutation > Neuroendocrine > PGL > PGL2 > SDH > Saccharomyces cerevisiae > Science TV > Sdh5 > Sdh5 protein > blood vessel > blood vessels > cellular functions > chemical reaction > hSDH5 gene > paraganglioma > succinate dehydrogenase
Fingerprint' technique spots frog populations at risk from pollution
27.03.2017 | Lancaster University
Parallel computation provides deeper insight into brain function
27.03.2017 | Okinawa Institute of Science and Technology (OIST) Graduate University
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
27.03.2017 | Earth Sciences
27.03.2017 | Life Sciences
27.03.2017 | Life Sciences