A report on this discovery will appear in the February print issue of Nature Genetics.
The joint finding of the SCA5 mutation comes over a decade after initial speculation that Lincoln might have suffered from Marfan disease. People with this inherited disorder are often tall and thin and can commonly have slender, tapering fingers. The identification of the Marfan gene at Hopkins (Nature 352, 279-81 [1991]) sparked debate concerning testing of President Lincoln's DNA to determine whether his tall stature could have been caused by that disease.
The present discovery in Lincoln's descendants of the gene that causes a movement disorder called spinocerebellar ataxia type 5 (SCA5), however, appears to offer much stronger evidence that the past president himself might have had SCA5, according to Jeffrey D. Rothstein, M.D., Ph.D., a professor of neurology and neuroscience and vice chairman for research in the Department of Neurology at The Johns Hopkins University School of Medicine. SCAs are neurodegenerative disorders that cause loss of coordination of limbs and eye movements, slurred speech and swallowing difficulties.
"Determining President Lincoln's status relative to SCA5 would be of historical interest and would increase public awareness of ataxia and neurodegenerative disease," Rothstein said. The finding also has wider implications because similar mutations might also be associated with other neurodegenerative diseases, the Hopkins researcher said.
The researchers discovered that SCA5 is caused by a mutation of the -III spectrin gene SPTBN2, which disrupts the ability of certain nerves in the cerebellum to respond normally to incoming chemical signals. Eventually, these nerves -- called Purkinje cells -- degenerate, and the person loses fine control of the leg and arm muscles. This would explain historical descriptions of Lincoln's uneven gait -- an early sign of ataxia -- according to the researchers. Ataxia is an inability to coordinate muscle activity in the arms and legs.
"The discovery by the team of the SCA5 mutations in 90 of 299 descendants of Lincoln could enable us to prove whether Lincoln himself carried the mutation by studying genetic material obtained from artifacts containing his DNA," said Rothstein, a co-author of the Nature Genetics paper.
The researchers found the mutation in all 90 affected individuals (ages 7 to 80 at time of exam) and in 35 descendants of Lincoln who had not yet started to show symptoms of SCA5 (ages 13 to 67 at time of exam), he said. The team also found two other types of mutations in -III spectrin 2 in a French and German family, respectively. The mutations found in the American, French and German families each affected a different part of the SPTBN2 gene, and thus knocked out a different part of the -III spectrin protein.
The mutation of the SPTBN2 gene disrupts the normal shape of -III spectrin, a protein that is key to the proper functioning of Purkinje cells, according to Rothstein, who cloned the protein in 2001 and first described its role in the brain. Specifically, -III spectrin helps to anchor another protein, called "glutamate transporter EAAT4," into the membrane of the Purkinje cell.
In the current study, the investigators showed in isolated cells that EAAT4 tends to migrate rapidly through the membrane of Purkinje cells. This movement disrupts the ability of the nerve-signaling chemical glutamate to bind with EAAT4, Rothstein said. "The loss of the ability of -III spectrin to anchor EAAT4 in place so it can respond to glutamate could lead to signaling abnormalities over time," said Rothstein. "And over time, that could cause Purkinje cell death and lead to the symptoms of SCA5."
A further implication of these findings is that SCA5 mutations could affect the complex movement of proteins in other nerve cells, the researchers said. Specifically, the spectrin's interaction with a molecular "motor" that shuttles proteins through the cell suggests that mutated forms of this protein would disrupt this critical function.
The motor, which transfers proteins along cellular highways called microtubules, as well as glutamate transporters are implicated in a wide range of processes that are key to proper functioning of nerves, Rothstein noted. Disruption of the motor appears to occur in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), he added. ALS is a fatal disease involving the cells in the brain and spinal cord that control muscles. Motor disruption also occurs in Huntington's disease (HD), a genetic disorder that causes degeneration of brain cells in certain areas of the brain, resulting in uncontrolled movements, loss of intellectual abilities and emotional disturbance. In addition, disruption of protein transport through the long arms of nerves called axons occurs in Alzheimer's disease, he added.
"The results of our work and that of other researchers suggest that even though different -III spectrin mutations disrupt different cellular processes, all of these different disruptions eventually cause the death of a particular brain cell," he said. "So further studies of SCA5 will likely provide insight into molecular mechanisms common to SCA5 and other neurodegenerative diseases. In recent years we have discovered drugs that can modulate the glutamate transporter and its gene, and that research could someday be useful for treating patients with spinocerebellar ataxia."
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