OHSU researchers' discovery may help remedy a rare disease

Oregonian, The (Portland, OR)

September 21, 2005

Author: Andy Dworkin; The Oregonian

Scientists identify a gene that can cause Fanconi anemia, which kills most of its victims by age 20

Scientists studying the illness Fanconi anemia -- work closely tied to Oregon -- have new proof linking the rare disease to a DNA-repair system that probably helps most people stay healthy.

The work brings doctors a step closer to understanding the normal role Fanconi anemia genes play in helping cells divide. That knowledge should improve the odds of finding a treatment for Fanconi anemia, which kills most patients by age 20.

"The more you understand about how the molecular machine works, the better chance you have of designing a therapy," said Oregon Health & Science University researcher Maureen Hoatlin, who with OHSU's Stacie Stone helped find one of two genes that can cause Fanconi anemia. Their work is published in the current issue of Nature Genetics.

The new findings also strengthen a link between Fanconi anemia and mutations in BRCA genes, which increase a woman's risk of breast and ovarian cancers. Though researchers know enough to say the two problems clearly involve some of the same bits of biology, they don't know the exact links between the conditions.

Fanconi anemia is uncommon, affecting perhaps 500 U.S. residents at any time, including several Oregon families. The illness often causes birth defects and bone marrow problems. Sufferers also are at high risk of developing a form of leukemia and tumors in body regions where cells grow rapidly, like the throat.

People get the disease when they inherit mutant forms of a Fanconi anemia-related gene from both parents. Before the Nature papers, scientists knew of nine such genes. Children with two bad copies of any of those would get the illness. The new papers raise that number of genes to 11, and scientists think there are at least two more genes to find.

Many genes cause disease

"The thing about Fanconi anemia is that it is not just one disease. There are many different genes" that cause the illness, said Arleen Auerbach, a Rockefeller University scientist who helped find the newly identified gene known as BRIP1. Hoatlin's and her colleagues' gene is known as FANCM.

What all Fanconi patients share is a sensitivity to a kind of DNA damage called crosslinking. That happens when the four chemicals that dictate DNA's code -- the bases -- improperly stick together. When cells try to unzip and copy their twin DNA strands so they can grow, the fused bases don't separate properly, which can lead to broken DNA or mutant copies.

Auerbach said strands of DNA break "all the time" in people and other beings. If these breaks weren't fixed, life as we know it would crumble. So cells have a complex series of overlapping repair systems to find and fix DNA problems.

Because Fanconi patients commonly have problems with both strands of DNA breaking, scientists long thought a flaw in a system to repair those breaks caused the illness. But they did not know, for any of the nine identified Fanconi genes, exactly how those genes or the proteins they made interact with DNA strands.

The two newly identified genes change all that. Each of them physically connects to DNA as it splits apart and copies itself.

"Now we know, for the first time, Fanconi anemia genes are interacting with DNA itself," Hoatlin said. "With these genes, you actually have a window into what they are doing, which is unwinding DNA."

Protein has multiple roles

The FANCM protein, made by the gene Hoatlin helped find, seems to have three roles in the DNA replication process. It joins at least seven other proteins to make a "core complex," an intricate cellular machine. No one knows just what this machine does; but if any of its parts break, the Fanconi DNA repair system won't work.

The FANCM protein also seems to be able to hook onto DNA being copied and move the "core complex" along that genetic strand. And it can help signal when a mistake is happening in the DNA copying process.

Hoatlin said she plans to keep studying the Fanconi core complex, trying to figure out how all the proteins work in that cellular machine.

The BRIP1 protein that Auerbach and others found does not take part in the core complex but seems to interact with DNA if that complex has successfully formed. The protein is able to help split certain forms of linked DNA strands.

"It probably helps unwind it (DNA), in order for other genes to repair it," Auerbach said. None of the genes that actually help repair the DNA has been found, she added.

The BRIP1 protein also seems to interact with a protein made by BRCA1, a gene whose mutant forms make a woman more likely to get breast or ovarian cancer. A few years ago, scientists in Oregon and elsewhere realized that another such gene, BRCA2, was a Fanconi gene -- one scientists had been calling FANCD2.

While these links intrigue scientists, Auerbach cautioned that no one knows how adult breast or ovarian cancers might connect to the rare anemia. Many genes and proteins play multiple roles in the body, she noted, so they could cause the different illnesses in disparate ways.

Discovery inspires hope

The fact that scientists know 11 Fanconi genes shows amazing progress, considering the first gene was found 13 years ago, said University of Oregon President David Frohnmayer. He and his wife, Lynn, founded the Eugene-based Fanconi Anemia Research Fund in 1989 after learning their daughters had the disease.

"The progress is real and accelerating and of high scientific interest," he said. "It really gives us faith that we're on the right track."

Frohnmayer and his wife, Lynn, founded the fund in 1989 after having daughters with Fanconi anemia. Two of their daughters have died from complications of the illness: Katie, who died in 1991 at age 12, and Kirsten, who was 24 when she died in 1997. Their third daughter Amy, now 18, has the disease but "is very stable," her father said. She is starting her freshman year at Stanford University this week.

The Eugene fund has given grants to many of the scientists who have found Fanconi anemia genes, including the two recent discoveries. Frohnmayer said donations from Oregonians make up a big portion of the fund's income and help drive the research. Hoatlin, one of the researchers who has won grants from the fund, said, "It has really benefited this field and now cancer research in general."

Frohnmayer said the fund has helped doctors improve treatments. For instance, the foundation helped finance research into a drug that improves the success of bone marrow transplants from unrelated donors. Amy Frohnmayer will probably have that treatment when her health takes a turn for the worse.

Still, scientists don't know whether a drug can fix the complicated genetic defects driving Fanconi anemia. While some labs are starting to search for those medicines, others are exploring genetic treatments that attempt to insert healthy genes to compensate for the defective versions in patients' cells.

"Hopefully, the therapies will be in time" for today's patients, Frohnmayer said. "That's something you always find so wrenching. The basic science moves faster than the therapies."

Andy Dworkin: 503-221-8239; andydworkin@news.oregonian.com

Lynn and Dave Frohnmayer founded the nonprofit Fanconi Anemia Research Fund in Eugene. To contact the fund, write to 1801 Willamette St., Suite 200, Eugene, OR 97401, phone 541-687-4658 or go online to www.fanconi.org

To learn more about the disease, go to the National Institutes of Health: www.nlm.nih.gov/medlineplus/ency/article/000334.htm

Copyright (c) 2005 Oregonian Publishing Co.