BioWorld International Correspondent

LONDON - A collaborative effort by European and South African researchers has made it possible to identify the mutations responsible for a rare type of inherited anemia, and pinpoint the French settler who brought the mutant gene in question to Cape Town, South Africa, in 1688.

Fanconi anemia is a rare genetic disease that in Europe affects about three or four children born each year per million population. The Afrikaner population of South Africa, however, has the highest incidence of Fanconi anemia in the world, although it is still a rare disease, affecting about one in every 25,000 people.

The elucidation of the precise genetic defects present in the Afrikaner population will now make it possible to offer this group tests to detect carriers of these mutations, as well as prenatal diagnosis for couples who already have had an affected child.

An account of the study appears in the Proceedings of the National Academy of Sciences, titled "Molecular and genealogical evidence for a founder effect in Fanconi anemia families of the Afrikaner population of South Africa."

Fanconi anemia is a devastating disease. It causes anemia by the age of 6 or 7 years, which is fatal within about 12 years of diagnosis unless a matched bone marrow transplant from a relative can be carried out. Long-term survivors of this treatment are at high risk of developing squamous cell carcinomas during their 20s and 30s. The condition also is associated with congenital abnormalities such as absent thumbs, short stature, heart and kidney defects and small eyes.

The disease may result when two people who both carry the recessive mutant gene have children together. The risk of having an affected child is then one in four for each pregnancy.

Christopher Mathew, professor of molecular genetics at Guy's, King's and St Thomas" School of Medicine in London, told BioWorld International, "The chromosomes of children with this disease are very fragile, with many breaks. This suggests that the mutations result in a DNA repair defect. For this reason, our focus is now on trying to understand the function of the proteins encoded by these genes."

Although six different genes that, when mutated, result in Fanconi anemia have now been cloned, he said, nothing is known about what their protein products do. The group is now trying to identify known proteins that interact with those encoded by the Fanconi genes.

Ultimately, the goal would be to design rational drug therapy to correct the genetic instability and restore the normal activity of the gene. "Gene therapy protocols for the treatment of patients are also under development," Mathew said. "In principle, it should be possible to put a healthy copy of the gene into some of the patient's own bone marrow stem cells and then reimplant these cells. They should multiply, express the gene and correct the defect in the blood cells."

Initial studies showed this might be more difficult than it sounds, because numbers of stem cells in patients who have the disease are very low, he added.

The group began by looking for the Fanconi anemia group A gene, known as FANCA, because it causes two-thirds of cases worldwide. They started in South Africa because of the high incidence of the disease there and the ability to obtain family records.

All the Afrikaner patients they studied turned out to have the group A form of the disease. Further investigations showed that many of the patients had identical small variations in the DNA sequence close to the gene, known as single nucleotide polymorphisms.

Mathew said: "This information helped us to narrow down the region in which the gene was present, and identify the gene itself. We then sequenced the gene, and found that in many cases a large region of the gene was deleted. The majority of the Afrikaner patients had this one particular mutation, and the polymorphisms in these patients were exactly the same."

In all, the large deletion accounted for 60 percent of cases. This, plus another two mutations, were present in 80 percent of the patients studied.

This proved to Mathew and his colleagues that, as other researchers had already theorized, the high incidence of Fanconi anemia in the Afrikaner population was due to what is known as the "founder effect." Mathew explained: "We know that a small group of settlers went out to the Cape during the late 17th century and that the population established there remained fairly isolated for the next 300 years or so. If a carrier went out on one of the ships and was very fertile, producing several carriers among his or her children, and then for several hundred years these individuals and their descendents did not marry much outside their group, the mutant gene could achieve quite a high frequency in the population during this period."

Study of genealogical and other records revealed that the ancestors of all patients with the deletion mutation could be traced back to the family of a French Huguenot couple that landed in Cape Town in June 1688. This couple had 10 children, and the patients" families could be traced back to five of them, who presumably had all been carriers.

"Our working hypothesis," Mathew concluded, "is that there may have been two branches of this family with this mutation, one ending up on a ship to Cape Town and the other settling in Germany. We believe that it is the same mutation event because the background polymorphisms in the German patient are exactly the same as those in the Afrikaner patients."

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