Evidence for chromosome fragility at the frataxin locus in Friedreich ataxia

2015-08-27 20:55:14

MUTATION RESEARCH; 27 August 2015: DOI:10.1016/j.mrfmmm.2015.08.007

Daman Kumaria, Bruce Haywarda, Asako J. Nakamurab, William M. Bonnerb, Karen Usdin


Friedreich ataxia (FRDA) is a member of the Repeat Expansion Diseases, a group of genetic conditions resulting from an increase/expansion in the size of a specific tandem array. FRDA results from expansion of a GAA/TTC-tract in the first intron of the frataxin gene (FXN). The disease-associated tandem repeats all form secondary structures that are thought to contribute to the propensity of the repeat to expand. The subset of these diseases that result from a CGG/CCG-repeat expansion, such as Fragile X syndrome, also express a folate-sensitive fragile site coincident with the repeat on the affected chromosome. This chromosome fragility involves the generation of chromosome/chromatid gaps or breaks, or the high frequency loss of one or both copies of the affected gene when cells are grown under folate stress or as we showed previously, in the presence of an inhibitor of the ATM checkpoint kinase. Whether Repeat Expansion Disease loci containing different repeats form similar fragile sites was not known. We show here that the region of chromosome 9 that contains the FXN locus is intrinsically prone to breakage in vivo even in control cells. However, like FXS alleles, FRDA alleles show significantly elevated levels of chromosome abnormalities in the presence of an ATM inhibitor, consistent with the formation of a fragile site.


Friedreich ataxia (FRDA) belongs to a group of genetic conditions known as the Repeat Expansion Diseases. These diseases all arise from a poorly understood process that results in an expansion or increase in the size of a tandem repeat tract. In the case of FRDA the repeat unit is GAA/TTC and the repeat tract is located in the first intron of the frataxin (FXN) gene, a genesituated at 9q21.1. Expansion results in epigenetic modifications that down-regulate the transcription of affected alleles. The result of this downregulation is a progressive neurodegeneration that leads to gait and balance difficulties that often results in
patients becoming wheelchair-bound at an early age. FRDA has a high early mortality resulting from an associated hypertrophic cardiomyopathy.

All of the repeats associated with the Repeat Expansion Diseases form secondary structures that are thought to play a role in expansion and in some cases these secondary structures are also thought to be responsible for the underlying pathology. Those Repeat Expansion Diseases resulting from expansion of CGG/CCG-repeat tracts, such as Fragile X syndrome (FXS), are also associated with the expression of a fragile site coincident with the repeat. Fragile sites are often characterized as chromosomal regions with
constrictions, gaps or breaks that are visible during metaphase in cells grown in the presence of specific chemical inducers. One hallmark of these regions is that they are prone to chromosome rearrangement and translocation. Many fragile sites have been described in human genomes some of which are common, being found in large segments of the population, whilst rare fragile sites are only seen in a restricted group of individuals. The chemicals that induce fragility at a particular site are thought to reflect the properties of the DNA sequence of that site. For example, chemicals that affect the intranuclear levels of dCTP induce fragility at CGG/CCG-repeats, whilst A/T-specific DNA ligands such as distamycin A induce fragility at long A/T-rich repeat tracts. While the molecular basis of chromosome fragility is still not completely
understood, the prevailing idea is that individual loci are fragile because they are slow to complete replication, either because they impede replication fork progression in some way or are located in regions that only replicate slowly and late, and that this effect is exacerbated in the presence of inducers that further delay the completion of replication such that cells enter mitosis before replication is complete.While many categories of fragile sites have been described that are induced by folate-stress, distamycin, bromodeoxyuridine, 5-azacytidine oraphidicolin, it is possible that there are fragile sites for which a specific inducer has not yet been identified.

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Key Words

Friedreich ataxia | FXN | frataxin | repeat expansion | GAA/TTC-triplet repeat | chromosome fragility