The Long Stretch Gene

Earlier today we posted an excerpt from When A Gene Makes You Smell Like a Fish…and Other Tales about the Genes in Your Body, by Lisa Seachrist Chiu. Now we are going to delve deeper into the book with an excerpt that looks at a specific genetic disease, Marfan syndrome.

On January 24,1986, U.S. Olympic volleyball player Flo Hyman took a well-earned breather during a game her team was playing in Matsue, Japan. It was the third game of the evening, and Hyman rotated out on a routine substitution. She sat on the bench and within seconds slid to the floor. Just two years after her team made history winning a silver medal in Los Angeles, the woman touted as the best female volleyball player ever was dead.

Within an hour, physicians attributed her death to a heart attack. Her family, however, wasn’t convinced that a healthy athlete’s heart would simply give out, and they ordered an autopsy. Her family had been right; Hyman’s heart had been strong. The autopsy found that the major blood vessel leading away from it, however, was weak, and when it ruptured Hyman was dead in moments. As shocking as the death of this vital thirty-one-year-old was the cause: Flo Hyman had the genetic disorder Marfan syndrome.

Looking back, the towering six-foot-five Hyman had many of the outward signs of Marfan syndrome. Her height and slender build are characteristic of people with Marfan. Her long angular face and unusually long arms, too, were visible harbingers, as were the long, slender hands. Even so, those characteristics weren’t so unusual that her coaches or doctors noticed. Looking at her face you were likely to notice lively eyes and an electrifying smile. None of the other manifestations of Marfan syndrome particularly stand out among elite volleyball players who tend to be tall, lean, and long-limbed.

But it’s the less visible characteristics that are of particular consequence to the one in twenty thousand people in North America who have Marfan syndrome. In addition to pronounced lankiness, people with Marfan syndrome can have a laundry list of abnormalities, but it is the heart and blood vessel defects that are most lethal because they can lead to congestive heart failure and, as in the case of Flo Hyman, aortic rupture.

The problem for patients with Marfan syndrome involves connective tissue. This tissue serves as the structure and glue for the body, and includes such things as cartilage, ligaments, and the anchoring substance around cells called the extracellular matrix. In patients with Marfan syndrome, a critical protein used to build all connective tissue is defective, and as a result their connective tissues are just too stretchy.

Marfan syndrome was first described in 1896 by the French physician Bernard Marfan. He noticed a young girl whose arms, legs, fingers, and toes were long and thin compared to her torso. The girl also suffered from a curvature of her spine and poor muscle development. Shortly after Marfan identified the syndrome, physicians began to identify other characteristics of the condition. In addition to the symptoms already mentioned, patients may have a caved in or domed breastbone, overly flexible joints, flat feet, and a high, arched palate that causes their teeth to be crowded.

More than half of all Marfan syndrome patients end up with a dislocated lens of the eye, which can be slight or quite noticeable. People with Marfan syndrome also tend to be nearsighted and are at risk for early glaucoma and cataracts.

Most Marfan patients suffer not only from a weakened aorta but also from a mitral valve prolapse—where the valve between the upper and lower chambers on the left side of the heart billows out and causes blood to back flow from the lower chamber into the upper chamber. Mitral valve prolapse can be especially painful during times of stress. More serious is when the aorta widens where it attaches to the heart. As the aorta widens, the left ventricle—the lower chamber of the heart and its major pump—enlarges as it must pump even harder. Ultimately, the excess pumping force damages the heart muscle so severely that the patient develops congestive heart failure.

Scientists first began studying connective tissue in earnest in the 1950s, and Marfan syndrome was an obvious choice for analysis because the symptoms were so disparate but clearly related to connective tissue. Scientists were baffled by what possible defect was responsible for the changes in the aorta as well as the lens of the eye.

The first clue came from Lynn Sakai and colleagues at the University of Oregon Health Sciences Center. In 1986, the team discovered a protein they called fibrillin, which serves as the key component of a microfibril. Microfibrils are minute rodlike structures that can, in some tissues such as the aorta and ligaments of the musculoskeletal system, provide the framework for elastic fibers. In other tissues, such as the filaments that hold the lens in place in the eye, they have no association with elastic fibers at all. The common link between these two tissues is the fact that microfibrils have a remarkably uniform structure from one tissue to the next.

In 1991, a group of researchers from Oregon, Baltimore, and Boston—each taking a different tack honed in on the gene for fibrillin and simultaneously announced defects in the gene located on chromosome 15 were responsible for Marfan’s syndrome.

Marfan syndrome displays a typical characteristic of many single gene diseases: a single defect can have many effects on different areas and systems in the body. Geneticists call this “pleiotropy.” In the case of Marfan syndrome, the genetic defect readily explains why both the aorta and the lens of the eye are affected. It even explains how the limbs become so long: bone is covered by a connective tissue called the periosteum. Among other contributions to bone health, the periosteum provides an oppositional force to bone growth. When the periosteum is too stretchy, bone overgrows.

When the fibrillin gene was identified as the cause of Marfan syndrome, there was great hope in the medical community that it would lead not only to new therapies but also permit them to easily identify people with Marfan using a simple genetic test. Too many Marfan patients are diagnosed only after they’ve died from an aortic rupture, as Flo Hyman was. Unfortunately, creating that test hasn’t turned out to be so simple.

The fibrillin protein is large, and the gene encoding it even larger. The gene itself is more than two hundred kilobases in length, and the portion of the gene that codes for the protein is divided up into sixty-five different chunks called exons. The protein can only be made once the cellular machinery pieces those chunks together in the form of one contiguous strand of RNA. As a result, there are many opportunities for a mutation to occur. To date, there are nearly two hundred different mutations associated with Marfan syndrome, making it impossible to produce a simple genetic test for the disorder.

Still, researchers have been able to make efforts to use the genetic information to better understand the disease. For example, researchers have been correlating the genotypes of the mutations with the phenotypes presented in the disease. In general, missense mutations (changes to individual DNAbase pairs resulting in the protein being made with a different amino acid) have the most serious effects in Marfan syndrome. Harry Diete, a Howard Hughes Medical Institute scientist at Johns Hopkins University in Baltimore, Maryland, and colleagues found that this happens because the mutated fibrillin proteins bind to and disable the normal fibrillin. In other words, plenty of fibrillin is being made from the normal copy of the gene, but the protein made from the defective copy prevents the normal fibrillin from being deposited in the connective tissue the way it’s supposed to be. When a mutant protein actually prevents a normal protein from functioning, geneticists call it a “dominant negative effect.”

Because one defective gene causes this disease, scientists had been searching to find out what happens when a person inherits two defective copies of the fibrillin gene. Swedish researchers, led by Karl-Henrik Gustavson at the Medical Center Hospital in Orebro, Sweden, identified just such an anomaly in a newborn boy. The boy had inherited one mutant copy of the gene from his mother and a different mutant copy from his father. Unfortunately, that inheritance pattern proved devastating: the child was born with severe congestive heart failure and died by the age of four months.

Despite research into which mutations prove most deleterious, physicians still can’t predict which cases of Marfan syndrome will be the most severe based solely on genetic analysis. As a highly variable disease with a markedly visible phenotype, researchers and historians have speculated whether the condition has affected unusually tall individuals over the course of history. Historians have suggested that composer and pianist Sergei Rachmaninoff may have suffered from the disease but presumably benefited from an increased hand reach. Violinist Niccolo Paganini and Mary Queen of Scots have also been mentioned as potential Marfan sufferers. In the United States, the sixteenth president, Abraham Lincoln, has garnered the most questioning.

Lincoln was by all accounts a tall man. Exactly how tall no one knows, but as Phillip Reilly notes in his book Abraham Lincoln’s DNA, the photos of the president at the Antietam battlefield show him towering over all of the assembled military officers. Even so, when he was sitting Lincoln didn’t seem much taller than other men—most of his length was in his arms and legs. In addition, Lincoln was known to have astonishingly large feet as well.

The idea that Lincoln had Marfan syndrome took root after California physician Harold Schwartz diagnosed a boy with the condition and discovered the child was a descendent of Lincoln’s great great-grandfather Mordecai Lincoln. Schwartz published his speculation in 1962 in the Journal of the American Medical Association.

Schwartz’s hypothesis has been debated in the intervening decades, but when the gene for Marfan syndrome was discovered, suddenly there was the possibility that scientists could put the debate to rest. Their challenge now was to obtain something that contained Lincoln’s DNA. The National Museum of Health and Medicine in Washington, DC actually has such items in its collection: locks of hair, blood-stained clothes from the night Lincoln was assassinated, and other items. Extracting the DNA, however, would mean destroying at least a portion of whatever sample any researcher obtained.

Geneticist Darwin Prockop, then at the Jefferson Medical College in Philadelphia, jumped on the opportunity and requested permission in 1991 to obtain DNA from some of those stored samples in order to test the DNA for Marfan syndrome. The museum convened a panel of science and ethics luminaries (including Reilly, and Johns Hopkins University geneticist and Marfan expert Victor McKusick, who had •written extensively on Marfan syndrome) to consider the ethics and practicalities of the request. In May 1991 the panel delivered a “qualified green light” for the proposal based on privacy, ethics, and legal considerations. The question remained whether it was scientifically feasible to conduct such a test on valuable artifacts. In April 1992 the panel decided that it was not time to proceed with such testing because a simple genetic test didn’t actually exist, and the entire gene would need to be studied to make any determinations. In addition, the panel felt DNA extraction techniques weren’t adequately advanced to guarantee the maximal amount of DNA-would be recovered from any sample.

The request for Lincoln’s DNA-was one of the first attempts to reach back in history and use genetic information to answer nagging questions. But it certainly hasn’t been the last. Genetic analysis has been used on remains to determine if they were actually those of Butch Cassidy Pizarro, and Czar Nicholas of Russia. As genetic techniques continue to improve, the requests are likely only to multiply. Lori Andrews of the Illinois Institute of Technology and colleagues maintain that while the interest in such information is understandable, some ethical guidelines need to be in place for such inquiries.

At the same time, when reports of genetic diseases focus so heavily on the disability, patients with those conditions find great solace in learning important historical figures in some part shared their struggles and fate. For now, Marfan syndrome patients need only to look to Flo Hyman’s accomplishments for certain inspiration. Lincoln’s story may be answered later.