Zebrafish Provide Key to Unlocking Secrets of Fanconi Anemia

By Mark I. Levenstein

Published August 05, 2005, issue of August 05, 2005.
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The zebrafish, an inch-long fish indigenous to the Ganges River in East India and Burma, is proving to be a useful animal for understanding Fanconi Anemia.

Drs. John Postlethwait and Tom Titus of the University of Oregon’s Institute of Neuroscience told the Forward that they have almost completed mapping the protein sequence of the last of the nine known genes — at least 11 are suspected — that cause F.A. when mutated. They are doing this by studying the disease in zebrafish —a staple of aquariums.

“It looks like the zebrafish Fanconi system is virtually identical to the human system,” Titus said.

The research is considered exciting by other scientists. “By identifying the genes, we can deduce the exact sequences of the proteins they encode, discover where the proteins work and see if they are in complexes with other proteins we are more familiar with,” which will help explain the development of the disease, said Dr. Grover Bagby, an F.A. researcher at the Oregon Health and Science University.

F.A. is a recessive hereditary disease; the children of parents with mutations in the same F.A. gene have a 25% chance of developing the disorder. Although F.A. occurs in all ethnic groups, it is most prevalent among Ashkenazic Jews, who have a one in 87 chance of being carriers.

By affecting the DNA repair process, F.A. damages a “critical pathway,” said Titus, “because all of our cells make mistakes when they replicate.”

Sufferers of F.A. usually experience bone marrow failure and develop leukemia. Patients also have heightened susceptibility to other forms of cancer. F.A. patients are usually of small stature, tend to feel extreme fatigue and have frequent infections.

Previous studies have linked mutations in Fanconi genes to increased risk of pancreatic and breast cancers, meaning that even carriers, people with a single mutated Fanconi gene, might be at risk.

Experts agree that although humans and fish have been on separate evolutionary paths for 450 million years, the zebrafish is an ideal model for studying F.A. in humans. As vertebrates, zebrafish and humans have similar genomes, or sets of genetic information, implying that what occurs in a zebrafish’s DNA is likely to occur in a human’s, too. Zebrafish become sexually mature quickly, so the genetic makeup of subsequent generations is easy to change and the results of the changes become clear within the span of a few months. Zebrafish embryos also are transparent, rendering their internal functions easy to observe.

So far, every Fanconi gene that has been identified in humans exists in zebrafish as well. However, in addition to the nine known Fanconi genes, there are at least two more, referred to as “i” and “j,” which researchers have not yet located. “The best way to find them is to find human families that have [F.A.] and do genetic mapping studies in these families,” according to Postlethwait, who, with Titus, is doing his research under a grant from the Fanconi Anemia Research Fund.

“Once we have all the genes mapped, we can get on to the real work of understanding the disease,” said Dave Frohnmayer, the president of the University of Oregon, who co-founded the Fanconi Anemia Research Fund with his wife, Lynn.

FISHY BUSINESS: At left, a full-grown zebrafish. At right, a zebrafish embryo as studied by Fanconi researchers.






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