The researchers are from Australia, UK, Belgium and New Zealand’s Institute of Molecular Biosciences at Massey University.

Genetic mutations cause the disease

Queen Victoria

We have known for many decades that haemophilia B, known as the ‘royal disease’ because it plagued the descendants of Queen Victoria, is caused by a genetic mutation – to be precise, three different categories of mutations in the gene that produces clotting factor IX, which prevents excessive bleeding.

The first two categories of mutations were identified 20 years ago by Professor Merlin Crossley while he was at Oxford University in the UK. He found two sets of mutations that prevent two key proteins from attaching to the DNA, turning the gene off as a result. Interestingly, the symptoms of the disease 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.

Finding the key protein

Professor Merlin Crossley

Professor Crossley, and many other researchers after him, never gave up on the puzzle and have been trying to find the key protein associated with the third group of mutations (which accounts for more than half the cases of the disease). It remained elusive until very recently.

Professor Crossley, now Dean of Science at the University of New South Wales in Australia, led the team to prove the third and final piece of the genetic puzzle, but only after a hint from an unlikely source.

In a press release, Professor Crossley says 2 years ago he was on an aeroplane marking a young researcher’s PhD project. Data in the thesis reminded him of his own PhD project on haemophilia B Leyden, carried out at the University of Oxford in the late 1980s. He realised the young researcher was describing a DNA-binding site for a newly discovered protein that had a very familiar ring to it.

“I remembered it. It was the same sequence as for the binding site for the third group of mutations,” says Professor Crossley.

The results, published in March 2013 issue of The American Journal of Human Genetics, show that the newly identified protein in the PhD student’s work, called ONECUT, was indeed the missing piece in the puzzle of haemophilia B Leyden.

Curious scientists advance science

“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,” says Professor Crossley.

Although the new research will not alter the current method of treatment for people with haemophilia B Leyden, the researchers say it could eventually lead to new approaches to regulating genes in general for experimental or, ultimately, therapeutic purposes.

“Understanding the molecular regulation of the coagulation factor IX gene may aid in the development of therapies for other blood-clotting disorders such as thrombosis,” says another NSW researcher on the team, Dr Alister Funnell.