You may be aware of the recent story out of Austria, which culminated in the documentary “Mozart: The Search for Evidence,” on an ancient skull purported to be that of Mozart. DNA tests on the skull, which has been in the possession of the International Mozarteum Foundation in Salzburg, were inconclusive, as the tested skeletal remains thought to be that of Mozart’s maternal grandmother and niece turned out to be unrelated to each other, making any inference about the ‘Mozart’ skull impossible (you’d think they would get the result first, before committing to a TV documentary, but that’s another issue). In a recent op-ed piece in The New York Times, novelist Richard Powers notes that the remains of Mozart and Beethoven have been probed for years in hopes of learning something new about their life histories and their deaths. Powers comments:

Diagnosing art’s unsolved mysteries with state-of-the-art medical knowledge is irresistible….But what can the bones know that the notes don’t? Forget the forensics and face the music. The mysteries hidden in Mozart’s skull are everywhere for the hearing.

Agreed. And yet…

Human transmission genetics, by definition, is the study of history. All of this came to mind upon the recent publication in Nature Genetics by Ikeda et al. of the mutation underlying spinocerebellar ataxia type 5, a form of ataxia quite common in the descendents of Abraham Lincoln. This is far from the first time that the search for genetic disorders in Lincoln’s pedigree has been at issue. But in addition to advancing research in ataxia, it surely would be of more than passing interest if the 16th president of the United States were affected with ataxia, even if our appreciation of the Gettysburg and second inaugural addresses remain unchanged.

The senior author of the paper, Laura Ranum, comments on the 13-year-long search for the SCA5 gene:

In 1992 I received a phone call from a neurologist with an ataxia patient that had a strong family history of the disease. Impressed upon hearing there were at least eight affected family members, I asked if I could contact the patient directly. After talking to this woman about her family history she paused and said “but you know, you really ought to talk to my mother…I think she knows of some more cousins”; the SCA5 odyssey began. I called her mother, then her mother’s cousins, and their cousins. A common theme of these calls was that these family members all knew that they were related to President Lincoln, but not necessarily how they were related to each other or that there was so much ataxia in the family. After obtaining a few DNA samples and ruling out the SCA1 locus, Dr. Larry Schut, a neurologist working at the University of Minnesota, and I traveled to visit the family. Family members were very proactive, wanting to find the source of what they called “Lincoln’s disease”, and invited us into their communities and to family reunions, where we performed neurological evaluations and collected blood samples. Eager to brag about the family connection to Lincoln and also to increase awareness of ataxia, a family member arranged for the local newspaper to do an article about our research on our second of many trips. Although at the time we didn’t know that the disease went back as far as President Lincoln’s grandparents, because at that time we were only working with the branch of the family descended from President Lincoln’s uncle Josiah, the reporter wrote that we had traced the gene back to President Lincoln’s grandfather, Captain Abraham Lincoln. Embarrassing at the time, this inaccuracy proved serendipitous and fortunate because I was soon contacted by descendents of President Lincoln’s aunt Mary, who also suffer from ataxia. Dr. Schut and I went out to collect this branch of the family. Using DNA from both branches of the Lincoln family, we mapped the ataxia gene to the centromeric region of chromosome 11, a novel ataxia locus. The disease was designated spinocerebellar ataxia type 5 and the results were published in 1994 in Nature Genetics.

Although we had collected DNA from a considerable number of family members, we had very few recombinants because of the suppressed recombination near the centromere, and so our gene-rich critical region remained frustratingly large. Over the next decade, we continued to work with both branches of the Lincoln family, taking field trips almost annually—in what seemed to be an eternal search for the “key” recombinant. Dr. John Day joined the research effort in 1996, as part of an ongoing collaboration involving SCA8 and myotonic dystrophy type 2. Over the ensuing years, with many trips to examine family members and refine the clinical features of SCA5 we were able to collect and examine 299 family members, including 90 affected individuals with this slowly progressive neurodegenerative disorder.

Nine of the eleven known mutations that cause ataxia are microsatellite repeat expansions that result in anticipation. Because several children in the Lincoln family were significantly more affected than their parents, we initially screened microsatellite repeats found within the critical region. In 1999 and 2004, our colleagues in France (Drs. Alexis Brice, Alexandra Dürr and Giovanni Stevanin) and in Germany (Drs. Christine Zülke and Katrin Bürk) reported additional SCA5 families, which proved invaluable in proving that mutations in β-III spectrin cause SCA5 because the three families have distinct mutations.

An exciting realization for our group was that Dr. Jeffery Rothstein, from Johns Hopkins University, had previously shown that β-III spectrin (which his group referred to as GTRAP41) interacts with EAAT4, a glutamate transporter his group has been studying. Through a collaboration with Dr. Rothstein’s group we showed that mutant β-III spectrin fails to stabilize EAAT4 on the surface of the plasma membrane, which may lead to excitotoxicity.

The connection to President Lincoln has provided an opportunity to increase awareness of ataxia. To my amazement, the news of our discovery quickly traveled the globe in the popular press – the connection of this family to President Lincoln is clearly of interest to the world. I would like to thank the family for their participation and all of the collaborators on this paper, especially Yoshio Ikeda and Katherine Dick – co-first authors on this study. After years of study, I am thrilled we found the SCA5 mutation and eager to move forward with additional studies to understand how spectrin mutations cause disease and to relate these findings to mechanisms found in other neurodegenerative diseases.