28 January 2006. Spinocerebellar ataxias (SCAs) are a group of inherited neurodegenerative diseases that damage the spine and the cerebellum that sits just above it. The neuronal degeneration causes ataxia, or difficulty moving, which often manifests as poor gait, uncoordinated limb and eye movements, and slurred speech. It is ironic, then, that spinocerebellar ataxia 5 should be associated with one of the world’s most famous orators, U.S. President Abraham Lincoln. But a Nature Genetics paper, published online January 22, reports that 11 generations of families, going back over four score and seven years, inherited the disease from either the president’s uncle Josiah, or his aunt Mary. By extrapolation, Lincoln’s paternal grandfather, Captain Abraham Lincoln, or paternal grandmother, Bathsheba Herring, must have carried the SCA5 mutation. Whether the president himself might have been affected is questionable.
Laura Ranum from the University of Minnesota, Minneapolis, together with colleagues there, elsewhere in the U.S., and in Europe, identified the SCA5 mutation by analyzing samples from three affected families, one each in America, France, and Germany. The American family consisted of two main branches, one descending from Josiah Lincoln and the other from his sister Mary. First author Yoshio Ikeda and colleagues tested DNA from almost 300 Americans, 90 of them with symptoms of ataxia. The authors focused on a region of chromosome 11 that was previously linked to the disease, and by comparing genetic recombinations in this region, they pinpointed the mutation to a segment of less than three million bases, small enough for “shotgun” sequencing.
Ikeda and colleagues found that all of the affected Americans and 35 presymptomatic people had the same mutation, a deletion of 39 base pairs of DNA in the gene SPTBN2, which codes for a protein called β-III spectrin. The mutation ablates 13 amino acids in the third of three repeats. This is “likely to disrupt the highly ordered triple-α helical structure of the repeat, changing the overall shape of the tetrameric α-β-spectrin complex,” write the authors. The upshot is that spectrin III may fail in its job to stabilize the glutamate transporter EAAT4, and the glutamate receptor GluRδ2, which are normally found in the synaptic membranes of cerebellar Purkinje cells, where spectrin III is normally highly expressed. In fact, the authors found that in cultured cells, knocking out wild-type spectrin or adding in the mutant spectrin, altered the “gait” of EAAT4—the glutamate transporter, which normally sits quietly on the cell surface, became highly motile.
Ikeda and colleagues found that affected members of the French family had a different deletion, but it also affected the third of the three β-III spectrin repeats. The German family, on the other hand, had a simple single nucleotide switch, causing a leucine-to-proline change that “may disrupt the ability of spectrin to bind to the actin cytoskeleton,” suggest the authors. This, plus reports that spectrin may interact with dynactin/dynein motors that drive intracellular transport (see Holleran et al., 2001), suggests that SCA5 mutations could affect protein trafficking—a common theme in neurodegenerative diseases. In Alzheimer disease, for example, transport defects occur early in the pathology (see ARF related news story). Spectrin does not play a prominent role in AD research, though a small literature exists on its presence in amyloid plaques and in sprouting neurons in AD (e.g., Sihag & Cataldo, 1996; Masliah et al., 1991).
Photo credit: Laura Ranum and Nature Genetics
Wild-type spectrin (image on left) holds the glutamate transporter in place. A spectrin
mutant (image on right) underlying a rare, hereditary form of ataxia allows it to become
loose, and it jigs around in the membrane. Click on the images to see movies open in a new window.
As for President Lincoln, we may never know if he, too, carried the mutation because he has no living descendents to test, though there is anecdotal evidence to suggest he had an unsteady gait. According to Ikeda and colleagues, London Times reporter William Russell, describing Lincoln in 1861, wrote that “Soon afterwards there entered, with a shambling, loose, irregular, almost unsteady gait, a tall, lank, lean man….” But more importantly, Mendelian genetics dictates that his probability of inheriting the mutation was one in four. “The identification of the SCA5 mutation makes it possible to unequivocally determine if President Lincoln carried the mutation using artifacts containing his DNA,” write the authors. The purpose of this, they contend, would be to increase public awareness of ataxia and neurodegenerative disease.—Tom Fagan.
Ikeda Y, Dick KA, Weatherspoon MR, Gincel D, Armbrust KR, Dalton JC, Stevanin G, Durr A, Zuhlke C, Burk K, Clark HB, Brice A, Rothstein JD, Schut LJ, Day JW, Ranum LPW. Spectrin mutations cause spinocerebellar ataxia type 5. Nature Genetics. February 2006;38:184-190.