Written by Hillary Handler  Edited by Dr. David Bushart

How researchers found that SCA1 is caused by an expanded, repetitive DNA sequence – a discovery that has allowed for accurate SCA1 diagnosis and more focused research strategies

Before the true genetic basis of Spinocerebellar Ataxia Type 1 (SCA1) was discovered, researchers and medical doctors noticed that SCA1 causes motor dysfunction, death of specific types of brain cells, and premature death in affected patients. By assessing health outcomes in multiple families affected by SCA1, scientists also recognized that the disease is inherited in an autosomal dominant manner. This means that each person with an SCA1 diagnosis has a 50% chance of passing the disease to each of his or her children. In addition, researchers noticed that affected members of SCA1 families displayed a disease feature called anticipation: a trend of increasing symptom severity and earlier age-of-onset as the disease is passed from generation to generation. Despite these discoveries, the specific genetic mutation responsible for causing SCA1 had not yet been identified or described. Determining the genetic cause of an inherited disease is critical for allowing accurate diagnosis of the condition. Furthermore, understanding the genetics of SCA1 would provide researchers with important clues about disease pathology that could help with designing and developing treatments.

One of the groups that sought to identify the specific genetic cause of SCA1 was led by Dr. Harry Orr. These researchers published their findings in a landmark 1993 paper (Nature Genetics, 1993), which described the process by which they made their discovery. First, a technique called “linkage analysis” was used to determine the general location of the SCA1 gene within the human genome. By tracking how SCA1 is inherited relative to other, well-characterized genetic locations, the team was able to narrow their search to a small portion of chromosome 6’s short arm known as region 6p22-6p23. The researchers also noted that anticipation is often indicative of a particular DNA feature known as a trinucleotide repeat. To determine if a trinucleotide repeat was indeed causing SCA1, these scientists used DNA cloning and screening techniques within the identified region of chromosome 6. These experiments identified a CAG trinucleotide repeat within the SCA1 genomic target region of DNA.

After determining that SCA1 involves a CAG trinucleotide repeat, researchers compared the length of this repeat region between family members with and without the disease. With the help of the Southern Blot technique (which use electricity to separate DNA fragments by size), they found that people with a higher number of CAG repeats (longer DNA segments) in the SCA1 target region were more likely to develop the disease. Furthermore, among individuals who had SCA1, those with an earlier age-of-onset and those with more severe disease symptoms had longer CAG repeats than those with a later age-of-onset and/or less severe symptoms. Importantly, the expanded CAG regions were always present in individuals with SCA1. Together, these results indicate that the CAG trinucleotide repeat within the DNA of the SCA1 target region on chromosome 6 is the genetic origin of disease in SCA1.

Using DNA sequencing, researchers found that people unaffected by SCA1 had DNA sequences containing fewer than 36 CAG repeats, while individuals with the disease had more than 43 CAG repeats. Notably, the most severe cases and those with the earliest age-of-onset were those with the highest number of repeats. In support of the observation that SCA1 is a dominantly inherited disease, all the individuals with SCA1 had one normal allele and one abnormally expanded allele.

As a whole, this was a keystone paper in the field of SCA1 research. Beyond identifying the genetic basis of disease in SCA1, this study was also a testament to the importance of teamwork within the rare-disease community: this was a highly collaborative project involving research groups from multiple universities, several SCA1 families, and numerous physicians. Perhaps most importantly, the findings from this study have served as the basis for extensive continued SCA1 research as well as related work on other neurodegenerative diseases with similar genetic causes.

Key Terms

Allele: one copy of a particular segment of DNA. Generally, humans have 2 alleles for each gene: one maternal copy and one paternal copy.

Autosomal dominant: a condition caused by a mutation in one copy of the associated gene

CAG: a specific trinucleotide repeat seen in many dominant ataxias. Codes for the amino acid glutamine (Q).

Genetic anticipation: a trend of increasing disease severity and earlier age-of-onset as a condition is passed from generation to generation

Trinucleotide repeat: a stretch of DNA where three nucleotides (bases of DNA) are repeated successively, causing a stretch of the resulting protein to have repetitions of the same amino acid.

Conflict of Interest Statement

Hillary Handler is currently a graduate student in Dr. Orr’s laboratory at the University of Minnesota. She did not work on this specific project. David Bushart is a postdoctoral researcher at the University of Michigan and has no conflicts to disclose.

Citation of Article Reviewed

Orr, H.T., et al., Expansion of an Unstable Trinucleotide CAG Repeat in Spinocerebellar Ataxia Type 1. Nature Genetics, 1993. Jul; 4(3):p.221-6. (https://www.ncbi.nlm.nih.gov/pubmed/8358429)