Gene Identified For Most Common Form Of Fanconi Anemia

November 01, 1996

Gene Identified For Most Common Form of Fanconi Anemia
Prenatal diagnosis, gene therapy may be possible for this fatal, inherited disorder

The gene involved in the most common form of an inherited, often fatal disease called Fanconi anemia (FA), which causes severe bone marrow failure, birth defects and a type of leukemia, has been isolated and cloned by scientists in an international consortium of six centers, including The Rockefeller University. The work appears in the November NATURE GENETICS.

"The cloning of the Fanconi anemia gene will help develop a quick, accurate diagnostic test for about 65 percent of FA patients, as well as the approximately one in 300 people worldwide who carry a single copy of the faulty FA gene but do not develop the disease. Also, the information should assist in developing better FA treatments, even possible therapies, to correct the genetic mutations," says coauthor Arleen D. Auerbach, Ph.D., associate professor in the Laboratory of Human Genetics and Hematology at Rockefeller. Auerbach plans to discuss the findings during the Breakthrough Research Session of the American Society of Human Genetics Annual Meeting on Thursday, Oct. 31, at 7:30 p.m. (PST) in San Francisco, Calif.

Auerbach's laboratory at Rockefeller maintains the International Fanconi Anemia Registry, which contains information on 600 patients from around the world. The registry includes a database of genetic information on the patients, gleaned from studies of their blood samples, and their family pedigrees and health histories.

FA is a rare disorder, affecting several thousand people worldwide of all races and ethnic groups. The disorder severely reduces the production of blood cells in the bone marrow. As a result, a person with the disease is sometimes born with birth defects of the skeleton or kidneys or with mental retardation, but more commonly develops aplastic anemia or acute myelogenous leukemia, a type of cancer, during childhood or the teen years. FA usually leads to death by age 16.

Swiss physician Guido Fanconi first described the disease in 1927, based on his diagnosis of a family in which three boys had similar birth defects and blood disorders. Since then, researchers have identified at least five forms, known as FA-A through FA-E. The current paper reports the cloning of a gene, FAA, on chromosome 16 that mutates to cause FA-A, the most common form, accounting for up to 65 percent of FA cases. In 1992, scientists isolated the gene for FA-C, located on chromosome nine and responsible for 10 to 15 percent of FA cases.

Based on several studies, investigators suggest that the disease's many symptoms arise because the genetic mutations cause an increased sensitivity to agents that interfere with the structure of DNA in chromosones, causing chromosome fragility. The protein for which the FAA gene carries instructions also may have roles in DNA repair, cell cycle regulation and cell death.

The new research shows that the FAA gene carries instructions to make a protein that is not significantly like other known proteins, so it may "represent a new class of genes associated with the prevention or repair of DNA damage," according to the consortium scientists. In addition to Rockefeller, the consortium includes scientists from Adelaide Women's and Children's Hospital in Australia, San Giovanni Rotondo in Italy, Guy's Hospital in the United Kingdom, University of Leiden in the Netherlands and the Los Alamos National Laboratory in New Mexico.

Because FA is an autosomal recessive disorder, a person must have two copies of the mutated gene, one from each parent, to develop the disease. A person with one flawed FA gene does not have the disease, but can pass the gene on to his or her children.

"People who carry a single copy of the mutated FAA gene may carry clues to a range of disorders. If two copies of the faulty FAA gene leads to leukemia, birth defects and anemia, perhaps one bad FAA gene might make a person more susceptible or predisposed to such illnesses," says Auerbach. "With the new identification of the FAA gene, we can develop more precise screening tools to identify carriers and study their health over many years. Such data might provide information about cancers, birth defects and some blood disorders even more common that FA."

The best current treatment for FA is to replace a patient's diseased bone marrow. First, the marrow is destroyed with drugs and radiation. Then the patient receives a transplantation of new marrow from a healthy, genetically compatible donor. In 1989, Auerbach and her colleagues in Paris and Indiana showed that blood from a newborn's umbilical cord can be used instead of marrow. Both marrow and cord blood provide stem cells, which develop into healthy blood cells.

Previously, in 1981, Auerbach developed a blood test to determine whether children with only some FA symptoms, or even their normal-appearing siblings, actually were affected with the disease, a prerequisite to identify donors. However, while this test was a boon for identifying patients with two abnormal copies of the gene, it could not identify carriers of a single mutated gene, explains Auerbach.

A 1995 study had mapped the FAA gene to a section of chromosome 16, but not to a precise piece of DNA. The region also contained a recognized piece of DNA, which researchers call a marker and use as a reference point.

In the current study, the scientists used a molecular biology method known as positional cloning to isolate the FAA gene. First, using inheritance of additional DNA markers in family studies, the investigators narrowed their search to a region on chromosome 16 where the gene must be located. Genetic data from three generations of a Saudi Arabian FA family in the Rockefeller database and from 21 Afrikaner FA families enabled the gene hunters to determine that the FAA gene resides right near an end of chromosome 16.

After piecing together small fragments of cloned DNA, the scientists created a variety of maps of the entire region. Then, by comparing sequences of cloned DNA pieces from a healthy person with those from FA patients, the team determined that the patients' mutations result in a faulty FAA gene. This evidence proved that the gene isolated by the scientists was indeed the gene for FA-A.

The four different FAA gene mutations were found in patients of African-American, Italian and Northern European ancestry. Each mutation causes the removal of a different part of the FAA gene, scrambling its instructions to make proteins. The finding that three of the mutations were large deletions is surprising, the authors note, because most mutations in genetic disorders that are autosomal recessive are either very small DNA deletions or insertions or are point mutations, a specific error in the sequence of the nucleic acids that string together in the gene's DNA.

As a result, the FAA gene makes abnormal proteins that then malfunction in the subsequent cascade of biological processes involved in the development of different body systems, including making blood cells. Additionally, a section of this protein has a structure known to act as a signal to send a protein to a cell's nucleus, home of the chromosomes. Having such a signal suggests that the FAA gene's protein plays a direct role in DNA repair and duplication and the stabilization of chromosomes, the authors note.

The study received support from the U.S. federal government's National Heart, Lung and Blood Institute, part of the National Institutes of Health, and the Department of Energy. Other supporters include the National Health and Medical Research Council of Australia, Telethon-Italy, the Italian Ministry of Health, the Medical Research Council of the United Kingdom, the Fanconi Anemia Research Fund in the United States, the Cancer Research Campaign in the United Kingdom and the Dutch Cancer Society.

At Rockefeller, FA patients are evaluated at the Rockefeller University Hospital Clinical Research Center, the oldest such facility in the United States devoted solely to experimental medicine. FA patients and their families who wish to receive more information about the Rockefeller program or enroll with the International Fanconi Anemia Registry should call 212-327-7533 or send e-mail to

Established in 1910, the Rockefeller Hospital links laboratory investigations with bedside observations to provide a scientific basis for disease detection, prevention and treatment. This special hospital environment served as the model for the Warren G. Magnuson Clinical Center, opened at the NIH in 1953, and similar facilities supported by federal funding at more than 75 medical schools in the United States.

Rockefeller began in 1901 as the Rockefeller Institute for Medical Research, the first U.S. biomedical research center. Rockefeller faculty members have made significant achievements, including the discovery that DNA is the carrier of genetic information and the launching of the scientific field of modern cell biology. The university has ties to 19 Nobel laureates, including the president, Torsten N. Wiesel, M.D., who received the prize in 1981. Recently, the university created four centers to foster collaborations among scientists to pursue investigations of Alzheimer's Disease, human genetics, neurosciences and the links between physics and biology.
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