One Family's Search to Explain a Fatal Neurological Disorder
With their help, researchers are advancing the 70-year effort to understand—and treat—hereditary ataxia.
Identification of Gene Mutations
The field of ataxia research remained quiet for about 10 years. Dr. Larry Schut was practicing medicine in Golden Valley, Minnesota, but in the 1970s he received a phone call from the National Genetics Foundation regarding two brothers in Sioux Falls, South Dakota, who had a rare and incurable disorder. This phone call resulted in the diagnosis of 12 more people afflicted with SCA1 and the opening of several clinics sponsored by the National Ataxia Foundation. With a larger group of people to contribute to the research, Larry felt that there was new hope of identifying the underlying cause of SCA1. The Schut family assembled during a reunion, and Larry collected blood from the affected and unaffected members in attendance. In continuation of the genome association studies started by his uncle, Larry collaborated with Dr. Elving Anderson at the University of Minnesota. In 1984 they found a genetic region correlated with SCA1 located on chromosome 6. The region was near the human leukocyte antigen (HLA) complex, an area of the genome filled with many genes related to immune system function.
That same year, Larry recruited the help of one of us (Harry Orr) to zero in on the genetic region with which SCA1 was associated. At the time, Orr had been studying the HLA complex since 1976, was also trained in neuroscience and genetics, and had an interest in the SCA1 research. The Orr lab was well equipped to analyze the genetic region associated with SCA1, and they began work on genetic mapping of the region in 1985. Genetic mapping during these early days of molecular research was challenging, labor intensive, and limited by an incomplete understanding of the human genome. Larry helped by providing blood samples from family members and giving us a detailed family tree.
Our lab then used restriction fragment length polymorphisms (RFLPs) to reduce the genetic region in question. In RFLP mapping, size differences in DNA of the same region are identified by cutting at specific sequences with the use of particular enzymes. If a size difference was noted between affected and unaffected individuals, that region of the DNA was further scrutinized to see how the sequences differed. After almost 10 years of work on the project, we were able to reduce the genetic region in question down to a more manageable span that was associated with the disorder.
At this point we were close to a breakthrough, but we needed help to quickly hunt down the specific sequence of DNA responsible for causing ataxia. A phone call from Huda Zoghbi of Baylor College of Medicine, who was investigating the genetic cause of ataxia in a different family, started a 20-year scientific collaboration with us that still flourishes. Several Schut family members also volunteered their time by working in the lab, and Larry continued to collect samples and update the family tree. In 1993, our collaborative efforts paid off: A stretch of DNA that was much longer than the same stretch in unaffected individuals was isolated by RFLP mapping.
Subsequent analysis showed that the three-base sequence CAG, which codes for the amino acid glutamine, was repeated at this location in those with ataxia. Normally, this region of DNA has 28 to 35 CAGs repeated, interrupted by a sequence that codes for two other amino acids. In patients with SCA1, a mutation resulted in loss of this nonglutamine interruption and more than 35 uninterrupted CAG repeats.
The size of the repeat and the age of SCA1 onset were directly correlated—those with the longest repeats had the earliest onset of symptoms. The repeat disorder found in SCA1 is not unique; other well-known neurodegenerative disorders, such as Huntington's disease and amyotrophic lateral sclerosis, also derive from expansions in stretches of repetitive DNA. This discovery now linked ataxia studies to a much larger body of research on these other diseases. Once the mutation responsible for the development of SCA1 was discovered, researchers could generate a genetic test to identify carriers of the disorder so that family members could receive genetic counseling before conceiving children. Before the identification of the mutation, Larry had been tenaciously counseling presymptomatic Schut family members to wait to have children, and now only a handful of family members were potential carriers of SCA1. However, as SCA1 research gained more media attention, many other affected families were identified around the country. Although the development of a genetic test came too late for many of the Schut family members, it was life changing for other families affected by SCA1.
In 1994, the gene harboring the expanded CAG stretch that caused SCA1 was finally sequenced and named ATXN1 (commonly called Ataxin-1). ATXN1 is a large gene and is translated to protein in both the unaffected and disease versions. However, the protein produced in the SCA1 version is slightly different.
Researchers knew that the brainstem and cerebellum were the two areas severely affected in SCA1. Within the cerebellum, they discovered that Ataxin-1 protein was highly expressed within Purkinje cells, which are intricate and highly connected nerve cells critical for coordinating body movements. After they receive signals from planning centers of the brain, Purkinje cells sort out those messages and relay them through the spinal cord to muscles, causing movement. The underlying cause of the ataxia was degeneration of the Purkinje cells in SCA1 patients, and the mutation in Ataxin-1 was somehow involved in causing these cells to die.
Identification of the gene and mutation causing this rare form of ataxia was incredibly exciting for the Schut family and other families affected by SCA1, but many questions about the disease remained to be answered.