Unlucky strike, part two

Shahar Madjar, MD

Prince Alexei Romanov, a great grandson of Queen Victoria and an heir to the throne of the Russian monarchy was never a healthy boy. He suffered from severe bleeding beginning in infancy.

Like other male descendants of Queen Victoria, he was expected to follow the usual pattern: the royals died young. They died of excessive bleeding. They died of injuries others might have survived.

Prince Alexei did not die of a minor cut, or a slight bruise. Shortly after the Russian revolution had ended, on July 17, 1918, around midnight, the prince and all the other members of the royal family were awakened and ordered into the basement of ‘The House of Special Purpose’ where they were imprisoned by the Russian revolutionary forces. The execution squad of the secret police was brought in. Neighbors heard multiple gunshots from afar. The basement was filled with the smell of gunpowder. The prince was shot several times, then stabbed, but somehow was still alive. Yakov Yurovsky, the commander of the secret police, shot the prince, who was 13, twice more, in the head, to complete the mission. When the dust settled, when the cries of agony halted, the entire Romanov royal family – Tsar Nicholas II, his wife, and their five children – were dead.

The remains (skeletal bones) of the two youngest members of the Romanov family, Prince Alexis and his sister, Anastasia, were not discovered until 2007.

Evgeny I. Rogaev, a researcher at the University of Massachusetts and his colleagues carefully examined the remains of the Romanov family. They compared DNA extracted from the remains of the Romanov family to samples obtained from maternal and parental lineages of European royal families. They also compared the DNA to an archived 117-year-old blood specimen of Tsar Nicholas (when you are a Tsar, people tend to archive parts of your body, or just chop off your head). The researchers proved in an “accurate and unambiguous” way that the remains are indeed of the royal family.

Evgeny I. Rogaev went a step further. In a second article, published in the prestigious Science journal in 2009, he described how he and his collaborators applied genomic methods to sequence the DNA found in the remains of the royal family. This was not an easy task because the quantity of the DNA was small and of poor quality, but using sophisticated genomic processes, Evgeny overcame these obstacles. The researchers found a mutation located in the F9 (factor IX, or 9) gene consistent with a severe form of hemophilia B called Christmas disease.

Hemophilia is an inherited genetic disorder that impairs the ability of the body to form blood clots. Patients bleed excessively, even after minor injuries, into their joints and into their skulls.

Hemophilia is caused by a mutation in the gene encoding for factor VIII (hemophilia A) or factor IX (hemophilia B). Factor VIII and IX are two of several factors (or proteins) essential to blood clotting. A mutation in the gene (DNA) encoding for these factors can result in severely decreased amounts of these clotting factors. As a result, blood would not clot, and bleeding would not stop.

The history of the royal family and their royal disease demonstrates how hemophilia and similar diseases are transmitted. Scientists call this form of genetic transmission — caused by a mutation in the X chromosome — an X-linked recessive trait):

Humans have 23 pairs of chromosomes including one pair of sex chromosomes: XX in woman, and XY in men.

Queen Victoria was also born with 23 pairs of normal chromosomes. At one point in her life, however, a mutation had occurred in the DNA of one of her two X chromosomes. From that time on, the queen had one normal X chromosome and one defective X chromosome. Her gametes (eggs) contained either one or the other.

Queen Victoria’s daughters (XX) received one normal X chromosome from their father, and one X chromosome from their mother. They were not affected by the disease because the one normal X chromosome from their father was sufficient to encode for enough of the clotting factor. They had a 50 percent chance to inherit a defective X chromosome from the queen and be a carrier of the disease.

Queen Victoria’s male descendants (XY), on the other hand, received their Y chromosome from their father. They had a 50 percent chance of receiving a normal X chromosome and a 50% chance of receiving a defective X chromosome from their mother. And without a second, normal X chromosome to counterbalance the defective one, this royal descendants were doomed to suffer from the disease.

At times, one’s fate is determined not by one’s behavior, or the forces of nature or history, nor is one’s fate determined by the unique combination of normal genes inherited from his or her parents, but by a mutation that took place generations before — a single stroke of bad luck.

Editor’s note: Dr. Shahar Madjar is a urologist working in several locations in the Upper Peninsula. Contact him at smadjar@yahoo.com or at DrMadjar.com.