Unraveling the mystery
Ranum began her Lincoln family gene hunt in 1992 when she received a phone call from an Ohio physician who described a patient with familial ataxia. When she called the patient, the patient's mother, and several cousins afflicted with the disease, she learned that all were related to President Lincoln. Some even referred to the ataxia in the family as "Lincoln's disease."
Shortly after that, Schut and Ranum began to collect blood samples from the family. "It was obvious that the family had something different than SCA1," Ranum recalls. "They had a milder disease." They retained their mobility longer, lived longer, and suffered less severe cerebellar degeneration.
Laura Ranum, Ph.D., and John Day, M.D., Ph.D., led the research team that identified the gene responsible for a mild form of ataxia running in President Abraham Lincoln’s family. Lincoln himself had a 25 percent chance of carrying the mutation, Ranum says.
When a newspaper reporter in Louisville wrote a story about "Lincoln's disease," another offshoot of the family contacted Ranum. This time the relative was descended from President Lincoln's Aunt Mary. The identification of this second branch of the family means that one of President Lincoln's paternal grandparents must also have had the disease. And that, according to Ranum, means that Lincoln himself had a 25 percent chance of carrying the mutation.
In 1994 the University of Minnesota team mapped the gene to the 11th chromosome and named this newly discovered genetic form of ataxia SCA5.
Although the trips to Lincoln family reunions spanned more than a decade, the hardest part of the gene hunt was yet to come. Ranum and members of her lab studied the DNA contained in the blood vials collected from Lincoln's extended family. The search for this gene was particularly difficult because it fell near a tightly-packed region of chromosome 11 called a centromere.
"Sorting through the DNA in this sticky region of chromosome 11 made our search much more difficult," says graduate researcher Katie Dick. She and fellow researcher Yoshio Ikeda, M.D., Ph.D., patiently searched for this elusive gene for years.
In 2005 the group finally found what it had long been seeking: the specific mutation responsible for the Lincoln family's ataxia.
"Any family member with the gene will develop ataxia if they live long enough," Ranum says. "And their children have a 50 percent chance of getting it, too."
Eventually the researchers demonstrated that the mutation, an accident of chemistry, affects the function of another protein, called a glutamate transporter, that normally regulates how much stimulation the brain's neurons receive. Failure to control this stimulation leads to damaged neurons; in fact, it is what likely causes the death of the cerebellum cells. With the loss of enough of these cells, patients lose control of the movements of their legs, arms, and eyes.
Ranum's work opens the door to an entirely new cause of ataxia and suggests a new approach to studying the effect of genetic mutations on the brain.
"The discovery of this mutation supports the idea that over-excitation of the nerve cells is part of what's going on in ataxia, and that similarly damaged cells are possibly connected to ALS [Lou Gehrig's disease], Huntington's disease, and Alzheimer's," Ranum notes.
Ranum and colleagues from the University of Minnesota, Johns Hopkins University, the Hôpital de la Salpêtrière in Paris, and the Universities of Lübeck and Tübingen in Germany — along with Larry Schut, M.D. — published their findings on SCA5 ataxia in the January 2006 issue of the journal Nature Genetics.