MutLα Heterodimers Modify the Molecular Phenotype of Friedreich Ataxia

Abstract

BackgroundFriedreich ataxia (FRDA), the most common autosomal recessive ataxia disorder, is caused by a dynamic GAA repeat expansion mutation within intron 1 of FXN gene, resulting in down-regulation of frataxin expression. Studies of cell and mouse models have revealed a role for the mismatch repair (MMR) MutS-heterodimer complexes and the PMS2 component of the MutLα complex in the dynamics of intergenerational and somatic GAA repeat expansions: MSH2, MSH3 and MSH6 promote GAA repeat expansions, while PMS2 inhibits GAA repeat expansions.Methodology/Principal FindingsTo determine the potential role of the other component of the MutLα complex, MLH1, in GAA repeat instability in FRDA, we have analyzed intergenerational and somatic GAA repeat expansions from FXN transgenic mice that have been crossed with Mlh1 deficient mice. We find that loss of Mlh1 activity reduces both intergenerational and somatic GAA repeat expansions. However, we also find that loss of either Mlh1 or Pms2 reduces FXN transcription, suggesting different mechanisms of action for Mlh1 and Pms2 on GAA repeat expansion dynamics and regulation of FXN transcription.Conclusions/SignificanceBoth MutLα components, PMS2 and MLH1, have now been shown to modify the molecular phenotype of FRDA. We propose that upregulation of MLH1 or PMS2 could be potential FRDA therapeutic approaches to increase FXN transcription.

DNA Triplet Repeat Expansion and Mismatch Repair

“…Likewise, experiments in FRDA transgenic mice have yielded evidence supporting involvement of MSH2 , MSH6 , and MLH1 in promoting GAA·TTC repeat expansion (76, 77). By contrast, PMS2 -deficient transgenic mice display enhanced levels of GAA·TTC repeat expansion, suggesting that PMS2 plays a canonical mutation prevention role in this process (76, 78).…”

Repeat instability during DNA repair: Insights from model systems

“…However, in a DM1 mouse model, PMS2, the binding partner of Mlh1 in MutLα, is required for 50% of somatic expansions (Gomes-Pereira et al ., 2004). Despite the lack of a role for MutSα or MutSβ in intergenerationally transmitted expansions in the FRDA mouse (Bourn et al ., 2012; Ezzatizadeh et al ., 2012), Mlh1 is required for both germ line and somatic expansions (Ezzatizadeh et al ., 2014). Since PMS2 (MutLα), protects against expansions in this model (Bourn et al ., 2012) this suggests that there is also a role for MutLγ in FRDA expansions.…”

The Repeat Expansion Diseases: The dark side of DNA repair

“…MutLα has been implicated in at least 50% of somatic expansions in a DM1 mouse model [72] but seems to be excluded from a role in expansion in the FRDA mouse [69]. MutLγ is required for all somatic expansions in an HD mouse model [73] and perhaps, by inference, in a FRDA mouse model as well [69, 74]. The importance of MutLγ is consistent with the observation that MutSβ is required for expansion in most mouse models and the fact that MutLγ is thought to interact with MutSβ but not MutSα [75].…”