The study will appear online during the week of Sept. 14, 2003, and is scheduled for publication in the October 2003 edition of the journal Nature Genetics.
Scientists found that inactivation of the newly discovered protein, PHF9, disables the function of the FA pathway, a network of proteins that appears to be critical for many cellular processes, including repair of damaged DNA, blood development and fertility.
"What's intriguing about the proteins in the Fanconi pathway is that they don't contain familiar sequences, so until the discovery of PHF9, there have been very few clues about how they actually function," said Maureen Hoatlin, Ph.D., assistant professor of molecular medicine in the Oregon Health & Science University School of Medicine, who worked to isolate and characterize the function of PHF9 with colleagues at the National Institute on Aging; Free University Medical Center, Amsterdam; and the Baylor College of Medicine.
The isolation of PHF9 demonstrates a new way of recognizing FA genes by using direct analysis of the components contained in the Fanconi protein complex, Hoatlin said. Previously, several Fanconi genes were discovered by finding their positions on chromosomes, or by going to a library of genes to select one that would correct the defects.
PHF9 is a member of a multicomponent Fanconi protein complex. It is believed to trigger the function of another FA protein, FANCD2, discovered and cloned in February 2001 by Markus Grompe, M.D., professor of molecular and medical genetics, and pediatrics in the OHSU School of Medicine. When the function of PHF9 is disrupted, FANCD2 is not modified, and the pathway short-circuits, leading to the disease hallmarks of FA.
"Finally, a Fanconi protein with a recognizable catalytic function," Hoatlin said. Unlike the majority of other Fanconi proteins, PHF9 has easily recognizable functional domains that should accelerate research aimed at understanding the function of the FA protein network, particularly in the maintenance of a stable genome, the "hard drive" of the cell where genetic information is stored.
Fanconi anemia is a rare, genetic cancer-susceptibility syndrome. When both parents carry a defective or mutated FA gene, children are at increased risk of developing the disorder, which can lead to birth defects, bone marrow failure and increased incidence of cancer, including leukemias and solid tumors. In addition, there is a growing appreciation among scientists that the FA pathway is integrated with the breast-ovarian cancer-susceptibility pathway.
Scientists estimate that the worldwide carrier frequency for Fanconi anemia is between 1 in 600 and 1 in 100, according to the nonprofit foundation Fanconi Anemia Research Fund Inc.
Dave Frohnmayer, who with his wife, Lynn, formed the Fanconi Anemia Research Fund after losing two daughters to the disease in the 1990s, called the PHF9 isolation study "a major discovery." He said it will thrust FA research into the mainstream of science, and its results have the potential to benefit not just dozens, but millions of people.
"This discovery has worldwide significance," said Frohnmayer, president of the University of Oregon in Eugene. "From day one, Oregon Health & Science University has been on the ground floor of Fanconi anemia research, so this is yet another welcome discovery by outstanding scientists."
The Fanconi Anemia Research Fund, as well as the National Institutes of Health, funded portions of the Oregon PHF9 work.
Frohnmayer has seen the number of FA studies increase dramatically in the last two years as more and more people discover that it is not just a rare, orphan disease. The PHF9 project "shows there may be an even more fundamental connection not only to cancer-causing processes, but to human aging processes generally."
"It shows that the research discipline intersects with new material in very unexpected ways," he added. "And often times, some of the greatest discoveries are the unexpected ones."
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