Large interruptions of GAA repeats in the frataxin (FXN) gene are very rare among patients with Friedreich’s ataxia (FA), a study has found. However, when these are present, it may be of importance to disease progression, researchers say.
The study, “Large Interruptions of GAA Repeat Expansion Mutations in Friedreich Ataxia Are Very Rare,” was published in Frontiers in Cellular Neuroscience.
FA is a rare, genetic, progressive disease that affects the nerves and muscles. Initially, patients notice an unusual loss of balance that gradually progresses to a complete loss of control of body movements, a medical condition known as ataxia.
The disease is caused by the repetition of three nucleotides — the building blocks of DNA — one guanine (G) and two adenines (A), in the first intron (a region of the gene that does not encode for a protein) of the FXN gene. In healthy individuals, GAA repeats normally range from six to 27, but in FA patients, these repeats can go from 44 to 1,700.
In most cases, GAA repeats are “pure,” that is, they remain together, one after the other, in the gene sequence. However, they can also be “interrupted” and be separated from each other “with regions of non-GAA sequence” in-between them.
In this study, researchers from the Brunel University London and collaborators set out to investigate the frequency of large interruptions in GAA repeats in FA patients.
The large-scale study analyzed 245 DNA samples — 238 from FA patients and seven from GAA repeat carriers. Investigators used a technique called polymerase chain reaction (PCR) to amplify GAA repeats and digested the amplified fragments with a restriction enzyme (a special protein that cuts DNA in specific spots) called MboII to detect the presence of interruptions.
Results showed that in 97.8% of FA patients, MboII digestion profiles were normal, suggesting that either GAA repeats were “pure” or contained very small interruptions invisible to digestion with the enzyme.
“Overall, our findings indicate that most [Friedreich’s ataxia] patients appear to carry primarily pure GAA repeat expansions [and are therefore more] likely to exhibit a classical FRDA phenotype [associated to severe] disease progression,” the researchers stated.
Conversely, patients with interruptions in GAA repeats normally have “a less severe FRDA disease progression, which may suggest a prognosis of milder disease.”
“Ultimately, future studies that enable GAA repeat expansion sequence verification at the base pair resolution are needed to allow further in-depth conclusions to be made regarding the importance of GAA repeat interruptions and FRDA disease,” they concluded.