The Discovery of SCA1

In 1993, Dr. Harry Orr and Dr. Huda Zoghbi identified the genetic cause of spinocerebellar ataxia type 1 (SCA1), marking an important milestone in the study of inherited neurological disorders. Their discovery was made possible through the use of linkage analysis, a genetic mapping technique that examines how specific DNA markers are inherited within families affected by a disease. By analyzing multiple generations of families with SCA1, researchers were able to link the disorder to a specific region on the short arm of chromosome 6, narrowing it down to 6p22–6p23. Once the candidate region was identified, researchers examined genes within this area and discovered a CAG trinucleotide repeat expansion within the ATXN1 gene. Trinucleotide repeats consist of short DNA sequences repeated multiple times, and while they are normally stable, excessive repetition can disrupt gene function. In this case, the CAG repeat encodes the amino acid glutamine, and abnormal expansion leads to the production of an altered ataxin-1 protein. DNA sequencing revealed that individuals with SCA1 carried more than 43 CAG repeats, whereas unaffected individuals had a much smaller number of repeats. This clear difference confirmed that repeat length was directly linked to disease development. Researchers also observed a strong relationship between the number of repeats and the clinical features of the disease. Individuals with longer CAG expansions tended to develop symptoms at a younger age and experienced more severe neurological decline, including progressive problems with coordination, balance, and speech. This relationship highlighted the role of repeat length in determining disease severity and age of onset. Additionally, studies showed that people with SCA1 possess one normal allele and one expanded allele of the ATXN1 gene. The expanded allele produces a mutant protein that accumulates in neurons, particularly in the cerebellum, leading to neuronal dysfunction and degeneration over time. This pattern of inheritance explains why SCA1 follows an autosomal dominant inheritance pattern. Overall, the discovery of the ATXN1 CAG repeat expansion not only clarified the molecular basis of SCA1, but also contributed to a broader understanding of trinucleotide repeat disorders.