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October 8, 2009. Copyright 2009, Graphic News. All rights reserved

Scientists pinpoint cause of "Royal Disease"

LONDON, October 8, Graphic News: It is well known that the "cursed blood" that afflicted descendants of Great Britain's Queen Victoria in the 19th and early 20th century was a form of the blood-clotting disorder haemophilia, but now new research published by Evgeny Rogaev and colleagues in the journal Science shows that it was probably a severe form of haemophilia B, the much rarer and more virulent form of the disease.

As an X chromosome-linked disease, the blood disorder is passed on through the maternal line but is manifested mostly in male descendants. Females carry two X chromosomes. If one is defective, the other chromosome compensates -- the woman's blood will coagulate normally but she can still pass the defective gene to her children. Males carry an X and a Y chromosome. If the X chromosome is defective there is not another to mask the disorder and haemophilia will show up in infancy.

The so-called "Royal Disease" first appeared in Prince Leopold -- the eighth of Victoria's nine children -- who suffered from severe bleeding throughout his life. However, it was through two of her five daughters, Beatrice and Alice, that the faulty gene was passed from Victoria to the royal families of Germany, Spain, and Russia.

In 1894 Nicholas Romanov, heir to the Russian throne, married Princess Alix, grand-daughter of Queen Victoria. Alix adopted the Russian Orthodox Church name, Alexandra Feodorovna. Nicholas II and Alexandra had five children, Olga, Tatiana, Maria, Anastasia, and their only son, Alexei.

In 1918, at the height of the Russian civil war, the entire Romanov family plus four of their servants were brutally murdered by the Bolshevik secret police in Yekaterinburg, a city 1,370 km (850 miles) east of Moscow. Their bodies were doused in acid and burnt before being buried in a forest outside the city.

The grave lay undiscovered until 1991 when a shallow pit containing skeletal remains of nine people was found. Forensic analysis confirmed that these remains belonged to members of the Romanov family and their attendants. However, the bones of two of the children were missing, leading to rumours that Alexei and one of his sisters, most probably Maria, had escaped the purge.

The mystery of the "missing" children was solved in 2007, when a second shallow grave containing semi-burned human bone fragments was discovered.

To identify the missing children and the exact nature of the defective gene 
Professor Rogaev and Dr. Anastasia Grigorenko at the University of Massachusetts Medical School extracted degraded DNA samples from the skeletal remains. Polymerase chain reaction (PCR) was used to multiply the DNA to usable amounts and Massively Parallel Sequencing (MPS) simultaneously screened thousands of loci -- specific locations of a gene -- to create maps of genetic mutations along the X chromosomes.

Comparing nuclear and mitochondrial DNA recovered from the fragments, Rogaev and his colleagues linked the remains to Alexandra, conclusively demonstrating that the bones in the 2007 grave belonged to 13-year-old Alexei and 19-year-old Maria. They also concluded that the Royal Disease was haemophilia B, caused by a mutation on the F9 gene within the X chromosome, and that one of the daughters, most probably Anastasia, also carried the defective gene.
/ENDS