Researchers at the University of California, San Francisco, havediscovered a new method of detecting a gene defect in about47 percent of people with severe hemophilia.

Jane Gitschier and her colleagues at the Howard HughesMedical Institute and Johns Hopkins School of Medicinereported the new diagnostic technique in the November issueof Nature Genetics.

Hemophilia A results from a defect in the factor VIII gene,which is encoded in the DNA of the X chromosome. Factor VIIIis the protein necessary for coagulation. Diagnosis of thedisorder is difficult because hemophilia involves manydifferent mutations of the factor VIII gene. The specificmutation for the severe form of the disease has not beendetected for nearly half of affected families. Hemophilia Aoccurs in about one in 5,000 males.

Gitschier said she and her colleagues found that a mutation inthe factor VIII gene occurs when a sequence in the intron (thenon-functioning region of the gene) is duplicated in genes nearthe factor VIII gene. The regions "within and outside the factorVIII gene recognize and exchange, or recombine, with eachother," Gitschier told BioWorld. "All the sequences in betweenthe two regions are inverted, thus disrupting the factor VIIIgene," she said.

Gitschier said this inversion, which has never before beenobserved, is estimated to occur in about 47 percent of familieswith severe disease, based on an analysis of 19 patients withsevere hemophilia.

The authors of the study said their findings "also suggest thatthe inversion detected by this assay is likely to occur de novoin many patients without a family history of hemophilia. Assevere cases account for approximately 50 percent ofhemophilia A, we suggest that inversions are likely to underlieat least 20 percent of all hemophilia cases."

The main benefit of this test is for detection of female carriersof the defective factor VIII gene, Gitschier said. She explainedthat it is a "marginal improvement" over the two existing bloodtests, and can be utilized with them.

The current coagulation test measures the amount ofcoagulation factor in a woman's blood. Gitschier said thatwomen who carry the defective gene have about half the levelof coagulation factor found in non-carriers. However, she notedthat some carriers have 70 percent of the coagulation factorand others 40 percent, while non-carriers can have 80 or 120percent of the coagulation factor. This overlap makes it difficultto make an accurate determination of whether a woman isactually a carrier.

The second test, link polymorphism, utilizes DNA markers.Gitschier said this test is very accurate, but it requires a lot ofinformation about pedigree that is not required with the test todetect for DNA inversion.

-- Brenda Sandburg News Editor

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