Discovery of the Marfan syndrome gene, whose existence was predicted 35 years ago by Dr. Victor A. McKusick, a Johns Hopkins cardiologist, is reported in today's issue of Nature, a British journal.
Scientists from Johns Hopkins and the Portland (Ore.) Shriners Hospital have proved that the gene responsible for making a connective tissue protein causes the syndrome, a potentially fatal, inherited disorder affecting one in 10,000 Americans, the journal reports.
The tall and long-armed Abraham Lincoln is believed to have had it. Olympic volleyball player Flo Hyman and University of Maryland basketball player Chris Patton died of it when their aortas -- the heart's major blood vessel -- burst despite apparently excellent health.
The finding is expected to have immediate use in early diagnosis of patients before symptoms appear and in prenatal diagnosis where the gene, which is altered in Marfan patients, can be tracked through families, says Dr. Harry C. Dietz, lead author of the Hopkins-Shriners Hospital paper, one of three related articles in Nature.
The gene is on chromosome 15 and normally makes the protein fibrillin, a component of connective tissue, the scaffolding that holds together skin, muscles and organs.
The mutated gene in Marfan's patients either makes too little of this scaffolding or makes weak or broken scaffolding. Since connective tissues exist everywhere in the body, a defective gene can affect a number of organs, but most commonly the heart, eyes, bones and skin.
The Hopkins-Shriners Hospital report shows that a particular alteration in the gene was present in patients with Marfan's and not in people without the syndrome.
"That was the final proof that the fibrillin gene was the gene responsible for Marfan syndrome," Dietz says.
The clustering of abnormalities that McKusick, a pioneer and world authority on Marfan syndrome and other connective tissue diseases, saw in some of his heart patients in the 1950s at Hopkins led him to determine that a single genetic defect in connective tissue must be behind the long arms and long legs, dangerous weakening of the aorta and dislocated eye lenses -- all characteristic of Marfan's.
The stretched, fragile aorta can rupture and cause sudden death and the dislocated eye lenses can lead to blindness.
Evidence suggests that the earlier a patient is diagnosed and started on medication, the better his or her chances of long-term, quality survival, says Dietz, a research geneticist.
"The real use for early diagnosis is in the individual who only has subtle features of the disease, but does have a family history," he says. "There are infants and children who don't show any signs of Marfan's syndrome, but they are from a family where the syndrome is passed along and then you have to make the decision: Is the child affected or not?
"In those individuals where it is not easy to make the diagnosis in early childhood, we can now make these diagnoses earlier."
To diagnose individuals who have a family history of the disorder, scientists identify a genetic marker in a family member who is known to have the syndrome and then determine whether it exists in other family members.
The discovery of the gene also will allow diagnosis in a fetus before birth, Dietz says.
"The precise indication for doing in utero diagnosis would be for families who are seeking family planning options," he says. "Basically, some people would decide to terminate a pregnancy if they knew they were carrying a child with Marfan's syndrome."
An offspring of a Marfan syndrome patient has a 50-50 chance of inheriting the disorder. However, spontaneous or non-inherited gene alterations are reported to account for 25 percent of cases. Scientists suspect that many more people have the disorder than are diagnosed.
The discovery of the gene is the culmination of almost 100 years of study of the disorder, which bears the name of a Paris pediatrician who first described skeletal abnormalities in a 5 1/2 -year-old girl in 1896.
Last year, a New England Journal of Medicine study by a Hopkins-Shriners team found that fibrillin is lacking in 90 percent of the Marfan syndrome cases. Later, a Finnish study mapped the Marfan syndrome gene to chromosome 15 and the Hopkins team placed it at a more specific location. Dr. Lynn Sakai and colleagues at Shriners cloned a portion of the gene that makes fibrillin, and localized it to chromosome 15, but its role had remained unclear.
"The next step is to look for more mutations or alterations and assess their role in the individual variation of the disease between and within families," says Dr. Reed Pyeritz, clinical director of the Hopkins Center for Medical Genetics. This will allow scientists to pursue new ways of rapidly screening families for all Marfan syndrome mutations.
McKusick, now university professor of medical genetics at Hopkins, is a key force behind the Human Genome Project, the international effort to map the human genome -- the genetic blueprint for a complete human being.
He is on a scientific panel that is interested in determining if President Lincoln had Marfan. The current plan is to use blood samples from the cuffs of the surgeon who dressed Lincoln's wounds in 1865, Dietz says.
"Those materials are available in the archives," he says. "The issue right now is whether those samples should be made available for this kind of an analysis." Government agencies will have to make that decision, he added.