New! Sign up for our free email newsletter.
Science News
from research organizations

New Gene Associated With Fanconi Anemia 'Explains' Hallmark Chromosomal Instability

Date:
August 22, 2005
Source:
Rockefeller University
Summary:
Surprising findings from just five patients has led to the first proof of how the rare disorder Fanconi anemia causes chromosomal instability. A team of international researchers, led by scientists at Rockefeller University, reports the findings in the September issue of Nature Genetics.
Share:
FULL STORY

Surprising findings from just five patients has led to the first proofof how the rare disorder Fanconi anemia causes chromosomal instability.A team of international researchers, led by scientists at RockefellerUniversity, reports the findings in the September issue of NatureGenetics.

The scientists found a gene mutation not previously known to berelated to Fanconi anemia, and they say that BRIP1 is the first geneassociated with the disease whose protein has a known function. Thatprotein, known as BACH1, normally helps DNA unwind in order to berepaired, and if it cannot function, chromosomal damage accumulates,they say.

"We have known for decades that patients with Fanconi anemiahave chromosomes that break easily, but none of the many genespreviously found to be associated with the disease explained thisphenomenon. This new link to BRIP1 mutations may have revealed acentral player in development of the disease," says the study'sprincipal investigator, Arleen Auerbach, Ph.D., who directs theLaboratory of Human Genetics and Hematology at Rockefeller. Workingwith her were researchers from two German universities and fromMemorial Sloan-Kettering Cancer Center in New York.

"Given these new findings, we can now suggest that DNAdouble-strand breaks are the lesions that underlie the pathology ofthis disease," says Auerbach, who is internationally known for her workon the disorder and for the large Fanconi anemia registry she maintainsat Rockefeller.

Fanconi anemia (FA) is an inherited disorder characterized bydevelopmental abnormalities, life-threatening bone-marrow failure, andpredisposition to a variety of cancers. Researchers have long knownthat patients with the disease have chromosomes that are not readilyrepaired when they break; in fact, a blood test created in 1981 byAuerbach, which uses a chemical that specifically increases thatdamage, is now used worldwide to diagnose FA.

Auerbach and others suspected this hallmark chromosomalinstability is associated with defects in caretaker genes that helpmaintain the integrity of DNA. One reason for this hypothesis is thatsome already identified Fanconi anemia proteins accumulated in thenuclei of normal cells along with protein produced by the gene BRCA1,which is believed to help maintain DNA stability, but when mutated, isthe major breast cancer susceptibility protein.

Researchers had theorized that the underlying fault in FA liesin the seven genes that need to work together to produce a protein"complex" that activates another existing cellular protein known asFANCD2. FANCD2 is then believed to work with BRCA1 protein to repairthe constant DNA damage that results from excessive sunlight,radiation, exposure to carcinogenic chemicals and even from normal celldivision.

"All of these seven Fanconi genes have to be normal -- if oneisn't, then FANCD2 is not activated," says Auerbach. But she adds thatno one knows what the proteins FANCD2, BRCA1 or even BRCA2 -- producedby another breast cancer susceptibility gene that has also been linkedto FANCD2 -- are actually doing.

"No one knows the precise role of any of these genes andproteins, but we believe that if BRCA1 or BRCA2, or any of the Fanconigenes that activate D2 are defective, a sequence of events is disruptedand DNA repair is blocked," she says.

But Auerbach and her team of researchers were puzzled thatabout 20 patients in the 1,000-plus International Fanconi AnemiaRegistry (IFAR) had no mutations in any of the genes known to beassociated with the disease, yet there was no question they had Fanconianemia. "These patients had the disease, yet their FANCD2 was activatednormally, and there were no problems with BRCA1 or BRCA2," she says.

So Auerbach and her colleagues selected four families for adetailed gene analysis, based on the suspicion that there was, in eachof the families, a "founder effect" -- a change in the frequency of agene mutation that occurs when a population is descended from only afew individuals. Two of these families were Inuit (aboriginalCanadians): one had two children with Fanconi anemia and the otherfamily had a single child with the disease. "We suspected there was asingle mutation in a single gene that affected these children,"Auerbach says.

The researchers also selected two Hispanic families in whichthey knew the parents were first cousins, and each had an affectedchild.

The researchers first applied a test that could tell themwhether the offending gene was "upstream" or "downstream" fromactivated FANCD2 -- that is, did action of the mutant gene fall in themolecular pathway before FANCD2 was activated, or after, respectively?The answer was that the problem was located downstream from a normallyfunctioning FANCD2.

The researchers then mapped SNPs in the genome of thosepatients and families, looking for changes in which a single chemicalbuilding block in the DNA differs from the usual building block at thatposition. Because FA is a recessive genetic disease, an affected childneeds to inherit two copies of an errant gene, each from a parent thatcarried a single mutation.

They were startled to find only one suspect location in theentire genome, on chromosome 17, that was present in all four families.Further research uncovered two candidate genes within that region, andnone of the patients had an abnormality in one of them. But they allhad mutations in the second gene, BRIP1.

"What was very surprisingly to us is that while all fivepatients were homozygous for a mutation in the gene, as expected, allhad the same mutation in this gene," Auerbach says. In other words, thefive patients each inherited two copies of the same mutation, one fromeach parent.

When the researchers looked at the other families in theirregistry with no known mutations in any of the genes associated withthe disease, they found six more patients with this same BRIP1mutation, three of whom were homozygous.

Now the story began to make sense to the researchers, since theprotein, BACH1, produced by BRIP1, was known to be a DNA helicase, aclass of enzymes which unwind the two strands of the DNA double helixso that DNA synthesis can take place. And they knew from the scientificliterature that BACH1 interacts with BRCA1 protein.

"This is the first gene associated with Fanconi anemia that wehave a defined function for," says Auerbach. "It interacts directlywith BRCA1, and is known to play a role in the repair of DNAdouble-strand breaks."

BACH1 could be the link between FANCD2 and BRCA1, the researchers say.

"It may be that DNA can't be repaired without a normallyfunctioning BACH1," says Auerbach. "So perhaps FANCD2 activation isn'tthe endpoint, as had been thought, but that it has to do somethingdownstream that can't be accomplished if BACH1 is not present."

###

The study was funded in part by grants from the National Institutesof Health, the Joel and Joan Smillow Initiative, and KinderkrebsklinikDuesseldorf. Contributing to the study are, from Rockefeller, firstauthor Orna Levran, Ph.D., Rashida Henry, M.S., Kelly Milton, B.A., SatDev Batish, Ph.D., Sandra Barral, Ph.D., and Jurg Ott, Ph.D.; ClaireAttwooll, Ph.D., and John Petrini Ph.D., from Memorial Sloan-KetteringCancer Center; Kornelia Neveling, B.S., Reinhard Kalb, B.S., and DetlevSchindler, M.D., from the University of Wuerzburg, Germany; and PaulaRio, Ph.D., Eunike Velleuer, B.S., and Helmut Hanenberg, M.D., fromHeinrich Heine University in Duesseldorf, Germany.


Story Source:

Materials provided by Rockefeller University. Note: Content may be edited for style and length.


Cite This Page:

Rockefeller University. "New Gene Associated With Fanconi Anemia 'Explains' Hallmark Chromosomal Instability." ScienceDaily. ScienceDaily, 22 August 2005. <www.sciencedaily.com/releases/2005/08/050821230248.htm>.
Rockefeller University. (2005, August 22). New Gene Associated With Fanconi Anemia 'Explains' Hallmark Chromosomal Instability. ScienceDaily. Retrieved November 10, 2024 from www.sciencedaily.com/releases/2005/08/050821230248.htm
Rockefeller University. "New Gene Associated With Fanconi Anemia 'Explains' Hallmark Chromosomal Instability." ScienceDaily. www.sciencedaily.com/releases/2005/08/050821230248.htm (accessed November 10, 2024).

Explore More

from ScienceDaily

RELATED STORIES