Article

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

ABSTRACT

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 is a rare, chronic, inherited bleeding disorder resulting from quantitative and/or qualitative deficiency of one or more plasma proteins (factors) of the clotting system. This disease is characterized by a deficiency in a specific clotting factor, resulting in the inability of the blood to clot normally and primarily affect males (Rogaev et al., 2009; Shastry et al., 2014). "

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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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    ABSTRACT: Over the past forty years the availability of coagulation factor replacement therapy has greatly contributed to the improved care of people with hemophilia. Following the blood-borne viral infections in the late 1970s and early 1980, caused by coagulation factor concentrates manufactured using non-virally inactivated pooled plasma, the need for safer treatment became crucial to the hemophilia community. The introduction of virus inactivated plasma-derived coagulation factors and then of recombinant products has revolutionized the care of these people. These therapeutic weapons have improved their quality of life and that of their families and permitted home treatment, i.e., factor replacement therapy at regular intervals in order to prevent both bleeding and the resultant joint damage (i.e. primary prophylaxis). Accordingly, a near normal lifestyle and life-expectancy have been achieved. The main current problem in hemophilia is the onset of alloantibodies inactivating the infused coagulation factor, even though immune tolerance regimens based on long-term daily injections of large dosages of coagulation factors are able to eradicate inhibitors in approximately two-thirds of affected patients. In addition availability of products that bypass the intrinsic coagulation defects have dramatically improved the management of this complication. The major challenges of current treatment regimens, such the short half life of hemophilia therapeutics with need for frequent intravenous injections, encourage the current efforts to produce coagulation factors with more prolonged bioavailability. Finally, intensive research is devoted to gene transfer therapy, the only way to ultimately obtain cure in hemophilia.
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