DNA trumps protein in Huntington onset

Mutant HTT DNA, not protein, could hold key to predicting and preventing Huntington disease onset

Two independent studies from former Teva CSO Michael Hayden and a Boston-based consortium suggest long, uninterrupted stretches of DNA repeats -- not the amino acids they encode -- could be the key to predicting and preventing the onset of Huntington disease.

Huntington disease (HD) is characterized by excess repeats of the DNA triplet CAG in the HTT gene. CAG encodes the amino acid glutamine in the HTT protein, but glutamine is also encoded by CAA. HD patients typically have CAA as the penultimate triplet in their HTT sequences, as these CAG series typically terminate with CAA-CAG.

Higher numbers of CAG repeats have long been correlated with earlier disease onset, but the assumption was this was due to the increased toxicity of the longer polyglutamine chains they encode.

But in an August Cell study and a June American Journal of Human Genetics paper, two teams independently showed HD patients with longer uninterrupted strings of CAG DNA repeats, such as those lacking a penultimate CAA, had earlier disease onset than patients whose CAG repeats were punctuated by CAA, despite having the same numbers of glutamines in their HTT proteins.

The results suggest age of onset is determined by the number of CAG repeats in HTT DNA, not polyglutamines in HTT protein, though they leave open the possibility that longer polyglutamine chains drive worse disease progression once symptoms have begun.

"It's a paradigm shift. It was always the polyglutamine length, and this is refocusing on the length of uninterrupted DNA sequence as most important," said AJHG study coauthor Hayden, who is director and senior scientist at University of British Columbia's Centre for Molecular Medicine and Therapeutics.

His team showed HD patients lacking a penultimate CAA sequence had a greater degree of repeat expansion in blood and sperm cells. The findings suggest uninterrupted CAG sequences are more genomically unstable than those punctuated by CAA sequences, and therefore more prone to accumulating additional CAG repeats, hastening disease onset.

The Cell study from the Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium led by James Gusella came to a similar conclusion via a GWAS of over 9,000 individuals.

Gusella is an SAB member of Triplet Therapeutics Inc., which is developing therapies for repeat expansion disorders including HD, and is director of Massachusetts General Hospital's Center for Human Genetic Research and professor of neurogenetics at Harvard Medical School.

In addition to showing that CAG length was the key predictor of age of disease onset, the GeM-HD Consortium found age of onset was modulated by variants of genes involved in maintaining DNA stability -- including mismatch repair regulator MSH3, nuclease FAN1 and DNA ligase LIG1 -- which it suggests could be therapeutic targets for the disease.

Hayden told BioCentury that if confirmed in larger data sets, the studies could have "profound implications" for HD diagnosis by providing more information about age of onset. "When patients are told they've inherited the mutation, the next question they ask is, when will it manifest?"

The results also raise the possibility of preventing or delaying HD onset by using gene editing or base editing to interrupt long CAG tracts by inserting CAA sequences. "Can you diminish the instability by adding additional interruptions? In the striatum, if you could limit the instability, you potentially could have some impact on disease expression," Hayden said.

His team is investigating the consequences of continuous and interrupted CAG sequences in broader HD patient populations, patient-derived induced pluripotent stem (iPS) cells and postmortem brain tissues, and is open to partnerships.

Targets: FAN1 - FANCD2 and FANCI associated nuclease 1; HTT - Huntingtin; LIG1 - DNA ligase 1; MSH3 - MutS Homolog 3

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