Genotype Analysis Identifies the Cause of the "Royal Disease"

University of Massachusetts Medical School, 303 Belmont Street, Worcester, MA 01604, USA.
Science (Impact Factor: 33.61). 10/2009; 326(5954):817. DOI: 10.1126/science.1180660
Source: PubMed


The "royal disease," a blood disorder transmitted from Queen Victoria to European royal families, is a striking example of X-linked recessive inheritance. Although the disease is widely recognized to be a form of the blood clotting disorder hemophilia, its molecular basis has never been identified, and the royal disease is now likely extinct. We identified the likely disease-causing mutation by applying genomic methodologies (multiplex target amplification and massively parallel sequencing) to historical specimens from the Romanov branch of the royal family. The mutation occurs in F9, a gene on the X chromosome that encodes blood coagulation factor IX, and is predicted to alter RNA splicing and to lead to production of a truncated form of factor IX. Thus, the royal disease is the severe form of hemophilia, also known as hemophilia B or Christmas disease.

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    • "Hemophilia B was distinguished from the more common hemophilia A in 1952, and was often referred to as "Christmas disease" after the last name of the first child described with this condition [3]. Hemophilia is sometimes referred to as “the royal disease”, because several members of royal families in Europe were affected by this scourge owing to the fact that Victoria, Queen of England from 1837 to 1901, was a hemophilia B carrier [5]. Her eighth son Leopold had hemophilia B, suffered from frequent hemorrhages and died of a brain hemorrhage at the age of 31. "
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    • "The newly generated AG dinucleotide can be engaged in splicing reactions when the distance with the natural AG is increased by $4 nt or when the natural site is mutated (Fig. 4), indicating that the natural 39 splice site prevents the use of the newly created 39 splice site. This is another peculiarity of intron 5 39 splice site region, because tandem AG dinucleotide arrangements frequently do not result in exon skipping but rather in activation of the mutant AG for splicing (as is the case of the hemophilia-causing mutation transmitted in certain European royal families; Rogaev et al. 2009). In addition, NAGNAG acceptors are very common in genes from a variety of organisms from land plants to humans (Hiller et al. 2004; Schindler et al. 2008). "
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