Interruptions in GAA Repeats Found to Delay FA Onset for 9 Years
People who have interruptions in a specific part of their GAA repeats in the FXN gene experience the onset of Friedreich’s Ataxia (FA) about nine years later than those without such breaks, a study found.
These findings highlight the importance of GAA repeat interruptions on the course of FA, according to researchers.
“The evidence presented here reinforces the need to account for the presence, and location, of interruptions in the GAA1 repeat tract and point to [certain] interruptions being a significant disease modifier [in] Friedreich’s ataxia,” the researchers wrote.
“Given the impact these findings have on the prognosis for patients, they are likely to enrich their genetic counselling,” they added.
Friedreich’s ataxia, a rare progressive disease that mainly affects nerve cells and muscles, is caused by excessive repeats of three nucleotides, the building blocks of DNA — one guanine (G) and two adenines (A) — in the FXN gene sequence.
Normally, GAA is repeated between five and 68 times. However, in FA patients, the GAA can be repeated from 66 to 1,700 times. These repeats cause an instability in the FXN mRNA — the intermediate molecule containing genetic information for protein production — leading to a deficient production of the frataxin protein.
Frataxin is important for the function of mitochondria, the energy-producing structures within cells, and its loss has a severe impact on the nervous system and muscles.
Generally, more GAA repeats are associated with less frataxin production, leading to an earlier age of symptom onset, more severe symptoms, and rapidly progressing disease. However, the number of GAA repeats can only explain about half of the variation in age of onset, suggesting that other mechanisms are in play.
Studies have discovered that GAA repeats can be interrupted by the insertion of other types of repeat sequences, including five to nine repeats of the GAGGAA sequence or 65 repeats of GAAGGA. In these cases, FA symptoms are either absent or mild with late-onset, suggesting that these interruptions may help stabilize the faulty FXN gene and lead to less severe disease.
Now, researchers based at University College London, in the U.K., investigated this phenomenon further by screening the DNA of 101 FA patients to find breaks in GAA repeat segments and explore the impact of these interruptions on the age of disease onset.
Blood samples were collected from FA patients, whose GAA repeat expansion size was already known.
Of the 101 FA participants, 72 (71.3%) had a break in the expansions at either the beginning of the GAA repeat section, referred to as a 5-prime interruption, or at the end of repeat expansions, called 3-prime interruptions.
In total, 19 patients (18.8%) had only 5-prime interruptions, while 32 (31.7%) had only 3-prime breaks. Breaks at both ends of the GAA repeats (5- and 3-prime double interruptions) were found in 21 individuals (20.8%).
Compared with patients lacking the double or 5-prime interruptions alone, the groups with 3-prime as well as 5- and 3-prime double interruptions had more patients with fewer than 350 GAA repeats in the FXN gene. Participants with only 3-prime interruptions had significantly fewer GAA repeats than those lacking the double interruption.
Patients with both 3-prime and double interruptions were significantly older at disease onset compared with the group lacking either 5-prime or 3-prime interruptions.
The team then conducted statistical modeling to understand how these interruptions influence the age at disease onset. Calculations found that the 3-prime interruption group had a median age at onset ratio of 1.623, which corresponded to a later age of onset than predicted for patients without a 5-prime or 3-prime interruption.
Participants with breaks at the end of GAA repeat expansions (3-prime) were predicted to have an age of disease onset 8.5 years later than those without 5- and 3-prime interruptions.
“This data indicates that patients with an [3-prime] interruption present with [Friedreich’s ataxia] approximately 9 years later than would be predicted for those lacking [5-prime and 3-prime] interruptions,” the researchers wrote.
“This highlights the key role of interruptions at the [3-prime] end of the GAA repeat tract in modulating the disease [characteristics] and its impact on prognosis for the patient,” they added.