Submitted on August 17, 2009
Accepted on September 28, 2009
Genotype Analysis Identifies the Cause of the "Royal Disease"
Evgeny I. Rogaev 1
*, Anastasia P. Grigorenko 2, Gulnaz Faskhutdinova 3, Ellen L. W. Kittler 3, Yuri K. Moliaka 3
1 University of Massachusetts Medical School, 303 Belmont Street, Worcester, MA 01604, USA.; Vavilov Institute of General Genetics RAS, Gubkina Street, 3, Moscow, 119991, RF.; Research Center of Mental Health RAMS, Moscow, 113152, RF.; Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, 119992, Moscow, RF.
2 University of Massachusetts Medical School, 303 Belmont Street, Worcester, MA 01604, USA.; Vavilov Institute of General Genetics RAS, Gubkina Street, 3, Moscow, 119991, RF.; Research Center of Mental Health RAMS, Moscow, 113152, RF.
3 University of Massachusetts Medical School, 303 Belmont Street, Worcester, MA 01604, USA.
* To whom correspondence should be addressed.
Evgeny I. Rogaev , E-mail: Evgeny.Rogaev{at}umassmed.edu
These authors contributed equally to this work.
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 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 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.
