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Spinocerebellar Ataxia Type 8: Lifetime risk and repeat interruptions

Written by Dr. Hannah K Shorrock
Edited by Dr. Larissa Nitschke

Differences in the lifetime risk of developing SCA8 are associated with the presence of interruptions in the ATXN8 repeat expansion.

In most spinocerebellar ataxias caused by repeat expansions, everyone who carries a repeat expansion above a certain threshold will develop the disease. In general, this coincides with individuals with a longer repeat being more likely to have an earlier disease onset. This is not the case for spinocerebellar ataxia type 8, or SCA8. Researchers in the laboratory of Dr. Laura Ranum wanted to know why some individuals who carry the SCA8 repeat expansion develop SCA8 disease, but others do not. In trying to answer this question, the researchers found that individuals who carry a particular type of interruption in their repeat expansion are more likely to develop SCA8 disease than those without it.

The lifetime risk of SCA8 disease

SCA8 is caused by a repeat expansion that sits within the overlapping genes ATXN8OS and ATXN8. In ATXN8OS the repeat expansion is a CTG, while in the overlapping ATXN8 gene, encoded by the opposite strand of DNA, the repeat expansion is a CAG repeat. Because of this, SCA8 can be said to be caused by a CTG·CAG repeat expansion in the ATXN8OS/ATXN8 genes. Despite clear evidence that this repeat expansion is linked to SCA8 disease, it does not cause disease in everyone who has the repeat expansion within their lifetime.

To understand more about how SCA8 disease presents, the team in Dr. Ranum’s lab studied the largest cohort to date of SCA8 patients. They found that the patients in their study had an age of onset ranging from birth to 79 years of age. They also found that despite the repeat expansion being inherited dominantly,  only 13% of families in the study presented with a typical dominant inheritance pattern of disease symptoms: at least one affected parent with 50% of children affected by the disease. For most families (82%), there was only one individual affected with SCA8 disease symptoms despite other family members also having the repeat expansion. These cases could be said to have a sporadic disease presentation. One final group of families, accounting for 5% of those in the study, presented with no affected parents, but multiple children affected by SCA8, despite the repeat expansion being present in at least one parent in each of these families. Together, these observations indicate that factors other than just the presence of the CTG·CAG repeat expansion in the ATXN8OS/ATXN8 genes influence whether an individual will develop SCA8 disease symptoms in their lifetime. So what are these factors?

To try to understand what influences whether individuals develop SCA8 disease, the group sequenced the ATXN8OS/ATXN8 repeat expansions in patients with SCA8 and individuals who were asymptomatic – people who have the repeat expansion but do not show symptoms of SCA8 disease. They found that almost half of the cohort had different types of sequence interruptions in their CTG·CAG repeat expansion. Of these, CCG·CGG interruptions were by far the most common. The researchers found that CCG·CGG interruptions were more common in SCA8 patients and families with multiple affected individuals than in asymptomatic individuals or SCA8 patients with no family history of the disease. Among individuals with CCG·CGG interruptions, there was a correlation between earlier age of disease onset and increasing numbers of CCG·CGG interruptions.

Together, these findings suggest that CCG·CGG interruptions are associated with an increased lifetime risk of developing SCA8 disease symptoms or an increased disease penetrance, versus someone with a pure CTG·CAG repeat expansion in the ATXN8OS/ATXN8 genes. The researchers use this finding to suggest a lifetime risk model for SCA8:

  • Individuals with a pure CTG·CAG repeat expansion in the ATXN8OS/ATXN8 genes may be at risk of developing SCA8.
  • Individuals with a CCG·CGG interrupted CTG·CAG repeat expansion in the ATXN8OS/ATXN8 genes may have an increased lifetime risk of developing SCA8.
  • Individuals with ataxia symptoms in line with the SCA8 disease, who do not meet genetic criteria for other ataxias, and have either a pure or CCG·CGG interrupted CTG·CAG repeat expansion in the ATXN8OS/ATXN8 genes likely have SCA8.

This guide should not be used by physicians as diagnostic criteria because these findings have yet to be replicated in independent studies and different patient populations. Instead, this new model is a starting point for more research into SCA8 diagnosis.

Herein lies the crux of the scientific method. One study does not have sufficient weight on its own. Studies must be replicated independently numerous times by the scientific community, before the scientific community will trust the proposed theory supported by the evidence presented. Only then would this new model have the potential to translate to clinically meaningful information for patients. And, even then, over time, that theory might change as new evidence is presented.

Why are CCG·CGG interruptions relevant to SCA8 disease?

The research group proposed that CCG·CGG interrupted CTG·CAG repeat expansion in the ATXN8OS/ATXN8 genes are associated with an increased penetrance of SCA8 disease. The researchers next asked why? Why would a CGG interruption in a CAG repeat tract make an individual more likely to develop the disease? To answer this question, the researchers turned to simple cell culture experiments and focused on the CAG expansion in ATXN8, because it is expressed about 7.5 times higher than the CTG expansion in ATXN8OS.

If you express a pure CAG repeat expansion in cells in culture, it causes some of the cells to die – in other words, it is toxic to cells. When researchers compared the toxicity of pure CAG repeat expansions to CGG-interrupted CAG expansions of the same length, they found that the CGG-interrupted sequences were more toxic to cells. This led the researchers to ask another question: how do CGG interruptions cause the CAG repeat expansions to be more toxic to cells? The answer, well, they found two possible explanations.

Explanation number 1: changing the sequence of amino acids. When CAG repeat expansions are found within a protein-coding region, they lead to the production of a polyglutamine tract in the protein. CGG interruptions encode a different amino acid – arginine. This means that CGG-interrupted CAG repeat expansions produce arginine-interrupted polyglutamine proteins. The research team showed that arginine-interrupted polyglutamine proteins are more toxic to cells than pure polyglutamine proteins and behave differently: arginine-interrupted polyglutamine proteins accumulate in specific regions of the nucleus called the nucleolus rather than being distributed evenly throughout the cell. This suggests that the arginine interruptions alter the localization of the polyglutamine proteins, which could contribute to the increased cellular toxicity of these proteins.

Explanation number 2: increased expression of repeat expansion proteins produced through repeat-associated non-AUG (RAN) translation. In SCA8, the CAG repeat expansion produces three different proteins. The polyglutamine protein, as previously mentioned, is coded for by ‘reading’ the CAG repeat expansion ‘in frame’. If the CAG repeat expansion is read out of frame, either as an AGC expansion or a GCA expansion, a polySerine or polyAlanine protein is produced. This occurs through a process called RAN translation. When the CGG interruptions are present, the researchers in this study found that increased levels of both polySerine and polyAlanine were produced. They proposed that this was due to the CGGs increasing the stability of the structures formed by the RNA, which are known to favor RAN translation. This suggests that an increased burden of disease-associated expansion proteins might contribute to the increased cellular toxicity of CGG-interrupted CAG repeat expansions.

What are the next questions for the reduced penetrance in SCA8?

In this study, the researchers showed that in families with multiple individuals affected by SCA8 disease symptoms, patients are more likely to have CGG interruptions. The team also identified six individuals that carried repeat expansions in both copies of their ATXN8OS/ATXN8 genes; all six individuals presented with SCA8 disease symptoms. This suggests that having two repeat expansions also increases the lifetime risk of developing SCA8 symptoms. The group, however, is still unable to answer why many individuals with a single pure repeat expansion do not develop SCA8 disease symptoms while others do. Future studies sequencing repeat expansions for more SCA8 patients may help to identify roles for the other interruptions on the penetrance of disease symptoms. Likewise, as larger cohorts of SCA8 patients are compiled, there is the possibility of performing genome-wide association studies to look at genetic variants in other genes that affect disease onset, progression, and even penetrance.

Key Words

Penetrance: The proportion of individuals carrying a particular genetic variant that also show the characteristic phenotype.

Amino acid: Amino acids are the individual building blocks that make up a protein and are simple organic compounds containing a carboxyl (—COOH) and an amino (—NH2) group. There are twenty standard amino acids used to make proteins by living cells and these are encoded by the genetic code.

Repeat Associated Non-AUG (RAN) translation: a protein production mechanism that happens without a start codon. RAN translation occurs when the mRNA contains a repeat expansion that causes the mRNA to fold into RAN-promoting secondary structures. Because RAN translation starts without an AUG start codon, the mRNA can be “read” in different ways.

Dominantly-inherited disorders: diseases in which a mutation in just one copy of a gene is enough to cause disease. For a patient with a dominantly-inherited ataxia, this means that there is a 1-in-2 chance that their children will inherit the disease-causing mutation (assuming that their spouse is unaffected).

Conflict of Interest Statement

The writer is co-first author on the manuscript this article is based on. The editor has no conflict of interest to declare.

Citation of Article Reviewed

Perez, B. A., Shorrock, H. K., Banez‐Coronel, M., Zu, T., Romano, L. E., Laboissonniere, L. A., … & Ranum, L. P. (2021). CCG• CGG interruptions in high‐penetrance SCA8 families increase RAN translation and protein toxicity. EMBO molecular medicine, 13(11), e14095.

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