UT Medical School microbiologist’s yeast-based research
provides key link to genetic explanation of liver failure
HOUSTON – (July 25, 2006)–Research performed on baker’s yeast in a University of Texas Medical School at Houston lab may help pave the way for life-saving gene therapy for families with a history of liver failure. A team of Italian geneticists recently succeeded in identifying the likely cause of a mitochondrial DNA depletion syndrome (MDDS) using key findings from 2004 research conducted by graduate student Amy E. Trott in the lab of Kevin A. Morano, Ph.D., assistant professor of microbiology and molecular genetics at the UT Medical School.
Kevin A. Morano, Ph.D
Mitochondria are present in nearly all living cells of higher organism, and they contain genetic material and enzymes required for cell metabolism. MDDS are genetic disorders characterized by a severe, tissue-specific decrease in the number of mitochondrial DNA copies, leading to organ failure and frequently death.
The Italian group, led by Drs. Antonella Spinazzola and Carlo Viscomi, studied three families with MDDS in an effort to determine what caused liver failure in their children. The findings, published in the May 2006 edition of Nature Genetics, identify mutations in the MPV17 gene as a new locus for hepatocerebral MDDS. The report extensively credits the work of Morano, who first characterized the yeast homolog of MPV17, previously linked to kidney disease in mice.
Discoverers of MPV17 in the early 1990s mistakenly concluded that the protein produced by the gene was located in the peroxisome, an organelle involved in metabolism, through their work with lab mice. However, Morano’s research established its actual location inside the mitochondria in yeast, and the recent Italian study confirmed that localization in human cells.
Morano’s study, published in the June 2004 Eukaryotic Cell, focused on heat shock, or stress, responses. All cells that experience severe environmental stress respond by activating a very conserved set of “heat shock” genes. Morano was looking for new heat shock yeast genes with human homologs through a project funded by the American Heart Association.
A single cell of baker's yeast, or Saccharomyces cerevisiae, is highlighted here in green. Bud scars, where "daughter" cells have budded off of the mother cell, are highlighted in blue. Baker's yeast is frequently used in molecular research because its cells closely mirror the genes and proteins within a human cell.
Baker’s yeast, or Saccharomyces cerevisiae, is frequently used in molecular research because it closely mirrors the genes and proteins within a human cell. Morano said that it’s also more cost-effective and easier to study than human cells. In its report, Morano’s group identified the yeast version of MPV17 and discovered that mutations in the gene they named SYM1 (stress-induced yeast MPV17) inactivated the mitochondria.
Relying on Morano’s findings, the Italian research team concluded from its sequencing work that all the sick patients in the study had mutations in the MPV17 gene and that those same mutations also inactivated yeast mitochondria. These findings provided a critical link between the yeast data and the sick patients.
“This is important because it’s very hard in the human genetics field to say ‘I found a mutation and it means something,’” said Morano. “But since we had an assay for the protein, (the Italian group) could exploit that to show that specific mutations in each sick child also fail to support yeast growth. They went on to demonstrate that, in yeast, those also showed mitochondrial DNA problems, which is exactly what was shown in the initial version of the clinical presentation,” he said.
Morano added that the Italian geneticists “were able to take the foundation that we laid working with simple yeast to explain in nearly complete biochemical and molecular detail this human disease.”
“This achievement illustrates the incredible value of the type of research quietly undertaken each day at the UT Health Science Center and in laboratories around the world,” noted Samuel Kaplan, Ph.D., professor and chairman of the Microbiology and Molecular Genetics department. “Collaboration across institutions and across continents, whether direct or indirect, advances research and moves us closer to solving scientific and medical mysteries,” he said.
Morano said he looks forward to seeing clinicians take the genetic findings and begin developing therapy options for patients affected by this type of organ disease. He is currently performing research on protein chaperone function in yeast with a $1.4 million National Institutes of Health grant that was awarded in April.
Amy Trott, who received her Ph.D. on May 6, 2006, said: "This study was an excellent opportunity for me as a student to develop skills and approaches in molecular biology that would allow for the application of basic science to questions relevant to clinical research."
She is doing postdoctoral research in molecular and cell biology at the University of California-Berkeley.
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