Age of Onset in Huntington’s Linked to Property of CAG Repeat Length in Study

Age of onset in Huntington’s disease is associated with a property of the inherited CAG repeat length in the huntingtin (HTT) gene — which determines the probability of further repeat expansions in nerve cells — rather than with the toxicity of the protein it produces, a study suggests.

Along with this discovery, which challenges accepted thought, its researchers also found that genes involved in DNA maintenance processes influence the disease’s age at onset, opening new treatment possibilities.

The study, “CAG Repeat Not Polyglutamine Length Determines Timing of Huntington’s Disease Onset,” was published in the journal Cell.

Huntington’s disease is caused by excessive repeats of a portion of DNA, called CAG triplets, within the HTT gene. This gene provides instructions to make the huntingtin protein. Each CAG triplet carries instructions to produce an amino acid (the building blocks of proteins) called glutamine.

Healthy people have up to 36 CAG repeats, and individuals with more than this number usually develop Huntington’s.  The length of the inherited CAG repeats in the HHT gene has been shown to determine the age at which motor symptoms appear in patients, with longer repeat expansions leading to earlier onset.

This has been thought to be associated with the production of more glutamines than normal — or polyglutamine — that disrupt the normal structure of the huntingtin protein and increase the likelihood of forming toxic aggregates.

Researchers’ findings here question this accepted theory.

Analyzing genetic data from more than 9,000 Huntington’s patients, they found a small number of people with changes in the region right after CAG repeats in the HHT gene.

Uninterrupted CAG repeats in HHT are usually followed by a sequence of CAA-CAG, but some patients lost the CAA triplet — which also contains the instructions to produce glutamine — and others had a duplication of that sequence.

People with an unchanged CAA-CAG sequence had two additional glutamines besides those from the CAG repeats; people without the CAA triplet had no additional glutamines; those with CAA-CAG duplication had four additional glutamines.

Knowing this, researchers could compare patients with an identical length of uninterrupted CAG repeats but with different polyglutamine lengths.

“The CAA-loss and CAACAG-duplication … allowed the role of uninterrupted CAG repeat length to be distinguished from polyglutamine length in determining age at onset,” they wrote.

Results showed that, compared with patients with CAA-loss, those with longer polyglutamine length associated with normal CAA-CAG sequence or CAA-CAG-duplication did not have an earlier-than-expected symptom onset.

Moreover, people with CAACAG-duplication consistently had later ages of onset, compared to those with CAA-loss.

“These findings indicate that the rate driver for the timing of [Huntington’s disease] onset lies in some property of the uninterrupted CAG repeat separate from its glutamine coding property,” the researchers wrote.

They emphasized, however, that this analysis does not exclude the role of polyglutamine toxicity in Huntington’s after the CAG repeat length has determined onset age.

Further analysis showed that age of Huntington’s onset was also associated with mutations in at least six genes involved in DNA maintenance and repair, which influenced age of onset depending on the length of the inherited CAG repeat.

These genes were suggested to be involved in non-inherited expansion of the HTT CAG repeats, a process known to influence onset, with the largest expansions leading to the earliest onset.

“Our data support the hypothesis that the critical property of the CAG repeat is its propensity to expand further as an individual ages, leading to longer and longer repeats in particular brain cells until a critical threshold length is reached and toxicity results,” James Gusella, a study author and a professor of neurogenetics at Harvard Medical School, said in a press release.

The results highlighted that both CAG repeats and DNA maintenance proteins that modify repeats expansion in nerve cells may be potential therapeutic targets to delay or prevent the onset of Huntington’s and other diseases associated with CAG repeats.

“A number of approaches are already being pursued to alter the length or purity of the [Huntington’s disease] CAG repeat and to develop drugs that [suppress] or activate particular DNA maintenance proteins,” Gusella added.