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Elongating expansions in HD and SCA1

Written by Dr. Marija Cvetanovic  Edited by Dr. Larissa Nitschke

Expanded CAG repeats are the cause of Huntington’s disease (HD) and several spinocerebellar ataxias (SCAs). Longer inherited CAG expansions correlate with the earlier disease onset and worse symptoms. We know from past research that these expansions are unstable and become longer from one generation to the next.

This study by Mouro Pinto and colleagues shows that repeat expansions also keep getting longer throughout life in patients affected with HD and SCA1 in many cells, including brain, muscle, and liver cells.

Expansion of CAG repeats in different human genes cause several neurodegenerative diseases. This includes Huntington’s disease (HD) and several spinocerebellar ataxias (SCAs). These long CAG repeats in disease genes tend to be unstable in the sperm and egg cells. This instability in sperm and egg cells can result in either longer repeat tracts (expansions) or shorter ones (contractions) in the children of affected patients. Unfortunately, CAG repeats more often expand than shrink. This results in a worse disease in the affected children, with earlier onset and more severe symptoms than their parents.

However, repeat instability and expansion of repeats are not confined to the sperm and egg cells. It can occur in many cells in a patient’s body. This ongoing expansion that occurs in other body cells is called somatic expansion.

Long CAG repeats in disease genes can be unstable and expand. Photo used under license by Enzozo/

As affected patients age, the ongoing somatic expansion, especially in the brain, may accelerate the onset of neuronal dysfunction and loss of neurons and. This may worsen the disease progression. This has been previously shown in mouse models and patients with HD. However, those studies examined expansion in only a few brain regions and tissues outside the brain (called peripheral tissues).

In this study lead by Dr. Vanessa C. Wheeler, the authors systematically examined repeat instability in 26 different regions of the brain, post-mortem cerebrospinal fluid (CSF) and nine peripheral tissues, including testis and ovaries from seven patients with HD and one patient with SCA1.

The authors found that both in HD and SCA1, CAG repeats expand more in the brain regions in the front of the brain, such as the hippocampus, a brain region involved in learning and memory, compared to the brain regions located more to the back of the brain, such as the cerebellum, the brain region involved in the coordination of movements. They also found instability in the peripheral tissues, including blood cells, skeletal muscle, and liver. Moreover, two factors contributed to longer expansion of CAG repeats in the brain: length of the CAG repeats inherited by patients and the time from the start of symptoms.

The authors have found a similar pattern of expansion in both HD and SCA1 tissues. As HD and SCA1 are caused by the CAG expansions in different genes, authors concluded that factors outside the affected genes play an important role in the specific pattern of CAG expansions.  

Additionally, it is quite interesting that the somatic expansions are not necessarily happening in the predominant sites of disease. In SCA1, one of the major brain region involved is the cerebellum. Still, there are not much somatic expansions happen in that area. This might indicate that somatic mutations do not play a major role in disease symptoms caused by cerebellar pathology in SCA1 but surely can affect them.

An important goal of this study was to assess whether CAG instability in accessible peripheral tissues might inform us of CAG instability in the brain. This includes skeletal muscle or biofluids (like blood or CSF). The authors found that CAG expansion in peripheral tissues and biofluids correlates well with that in the brain. This is an important finding as it indicates that changes in these peripheral tissues could be used as biomarkers in therapeutic trials testing drugs against somatic expansions.

Overall, this study sets the stage for future investigations to understand why CAG repeats are unstable and keep getting longer throughout life. They also showed how longer repeats contribute to disease pathogenesis. Lastly, they provided biomarkers for clinical studies to prevent somatic repeat expansion in the brain.

Key Terms

CAG-repeat diseases: A family of diseases caused by an expansion of glutamine amino acids in certain proteins. This includes Huntington’s Disease and forms of spinocerebellar ataxia.

Somatic Expansion: When CAG repeats expanded in the body and brain cells of people who have spinocerebellar ataxia, Huntington’s Disease, and other CAG triplet repeat disorders. Learn more about somatic expansion in this HDBuzz article.

Conflict of Interest Statement

The author and editor declare no conflict of interest.

Citation of Article Reviewed

Mouro Pinto, R. et al. “Patterns of CAG repeat instability in the central nervous system and periphery in Huntington’s disease and in spinocerebellar ataxia type 1.” Human molecular genetics 29.15 (2020): 2551-2567. doi: 10.1093/hmg/ddaa139. PMID: 32761094; PMCID: PMC7471505.

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