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Title: MutLα heterodimers modify the molecular phenotype of Friedreich ataxia
Authors: Ezzatizadeh, V
Sandi, C
Sandi, M
Anjomani-Virmouni, S
Al-Mahdawi, S
Pook, MA
Keywords: Friedreich ataxia (FRDA),;GAA repeat expansion mutation;Frataxin expression
Issue Date: 2014
Publisher: Public Library of Science
Citation: PLoS ONE, 9(6), e100523,(2014)
Abstract: Background: Friedreich 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 Findings: To 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/Significance: Both 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. © 2014 Ezzatizadeh et al.
Description: This article has been made available through the Brunel Open Access Publishing Fund.
ISSN: 1932-6203
Appears in Collections:Biological Sciences
Brunel OA Publishing Fund
Dept of Life Sciences Research Papers

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