Somatic instability of the expanded GAA repeats in Friedreich’s ataxia

Abstract

Friedreich’s ataxia (FRDA) is a genetic neurodegenerative disorder caused by transcriptional silencing of the frataxin gene (FXN) due to expansions of GAA repeats in intron 1. FRDA manifests with multiple symptoms, which may include ataxia, cardiomyopathy and diabetes mellitus. Expanded GAA tracts are genetically unstable, exhibiting both expansions and contractions. GAA length correlates with severity of FRDA symptoms and inversely with age of onset. Thus, tissue-specific somatic instability of long GAA repeats may be implicated in the development of symptoms and disease progression. Herein, we determined the extent of somatic instability of the GAA repeats in heart, cerebral cortex, spinal cord, cerebellar cortex, and pancreatic tissues from 15 FRDA patients. Results demonstrate differences in the lengths of the expanded GAAs among different tissues, with significantly longer GAA tracts detected in heart and pancreas than in other tissues. The expansion bias detected in heart and pancreas may contribute to disease onset and progression, making the mechanism of somatic instability an important target for therapy. Additionally, we detected significant differences in GAA tract lengths between lymphocytes and fibroblast pairs derived from 16 FRDA patients, with longer GAA tracts present in the lymphocytes. This result urges caution in direct comparisons of data obtained in these frequently used FRDA models. Furthermore, we conducted a longitudinal analysis of the GAA repeat length in lymphocytes collected over a span of 7–9 years and demonstrated progressive expansions of the GAAs with maximum gain of approximately 9 repeats per year. Continuous GAA expansions throughout the patient’s lifespan, as observed in FRDA lymphocytes, should be considered in clinical trial designs and data interpretation.

Onset features and time to diagnosis in Friedreich´s Ataxia

“…These ndings contradict the established correlation between GAA repeat length and disease milestones and suggest that these associations may be valid only when neurological symptoms are considered. Interestingly, cumulative evidence showed that GAA repeat expansions are subjected to somatic instability with accumulation of further contractions/expansions, which can lead to marked differences in the affected tissue and possibly explain lack of correlation between the course non-neurological symptoms and GAA1-repeat length (27). Eventually, we cannot exclude that the smaller number cases in the siblings´ group and in group with non-neurological onset contributed to the lack of signi cant correlation between age at onset and GAA1-repeat length.…”

Measuring peripheral nerve involvement in Friedreich’s ataxia

“…The exact pathogenesis remains unclear. However, tissue specific somatic repeat instability and selective tissue vulnerability likely contribute to the characteristic selective dysfunction of the central and peripheral nervous systems, heart, and pancreas . The predominant pathological involvement in the PNS occurs at the dorsal root ganglion resulting in a sensory neuronopathy .…”

DNA repair in trinucleotide repeat ataxias

“…FRDA is a (GAAGAA-GAA)n repeat expansion disorder in intron 1 of the frataxin gene on the positive strand of chromosome 9q21.11 leading to epigenetic changes within the frataxin gene, culminating in heterochromatin-mediated transcriptional silencing of the gene [25]. However, genetic modifiers may also account for the somatic instability of the expanded (GAA)n that drives disease progression [28]. Patients may also suffer from cardiomyopathy, optic neuropathy, skeletal deformity and diabetes mellitus.…”

“…As in SCA, age at onset and progression of FRDA partly depends on the TNR repeat length [27]. However, genetic modifiers may also account for the somatic instability of the expanded (GAA)n that drives disease progression [28].…”