Genetics of Hemophilia Mystery Solved

The third and final missing piece in the genetic puzzle of an unusual form of hemophilia has been found which could help improve the comprehension of other blood-clotting conditions such as thrombosis.

Hemophilia B Leyden is an X-linked recessive blood-clotting disorder that affects approximately 1 in every 30,000 males and it is also infamously known as the ‘‘royal disease’’ because it afflicted European royal families descended from Queen Victoria.

Geneticists at the University of New South Wales (Kensington, Australia) studied mutations that arise in coagulation factor IX (F9). Mutations within the F9 promoter are associated with the hemophilia B Leyden subtype in which symptoms ameliorate after puberty. Symptoms improve in young men after puberty because a different protein that responds to the hormone testosterone is able to bind to the DNA and boost the gene’s production of clotting factor IX. The disease affects about 80 families worldwide.

The scientists established that the missing regulators in hemophilia B Leyden are the ONECUT transcription factors ONECUT1 and ONECUT2. These proteins bind to the proximal promoter and drive expression of F9. ONECUT1 is also known as hepatocyte nuclear factor 6 (HNF6), while ONECUT2 is known either as hepatocyte nuclear factor 6-beta or one cut homeobox 2. The different Leyden mutations disrupt ONECUT binding to varying degrees in a manner that correlates well with their clinical severities.

Merlin Crossley, PhD, the dean of science at University of New South Wales and senior author of the study, said, “Science is advanced by people who get caught up in puzzles that are important to them and they never forget them. Curious investigators never give up.” Professor Crossley had previously found the two sets of mutations that prevent two key proteins from attaching to the DNA, which turns the gene off as a result. The study was published on March 7, 2013, in the American Journal of Human Genetics.

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University of New South Wales