title: MutLα heterodimers modify the molecular phenotype of Friedreich ataxia.
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.
  
  
  RESULTS
  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
  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.
authors: Division of Biosciences, School of Health Sciences and Social Care, Brunel University London, Uxbridge, United Kingdom.
authors: Vahid
authors: V
authors: Ezzatizadeh
authors: Division of Biosciences, School of Health Sciences and Social Care, Brunel University London, Uxbridge, United Kingdom.
authors: Chiranjeevi
authors: C
authors: Sandi
authors: Division of Biosciences, School of Health Sciences and Social Care, Brunel University London, Uxbridge, United Kingdom.
authors: Madhavi
authors: M
authors: Sandi
authors: Division of Biosciences, School of Health Sciences and Social Care, Brunel University London, Uxbridge, United Kingdom.
authors: Sara
authors: S
authors: Anjomani-Virmouni
authors: Division of Biosciences, School of Health Sciences and Social Care, Brunel University London, Uxbridge, United Kingdom.
authors: Sahar
authors: S
authors: Al-Mahdawi
authors: Division of Biosciences, School of Health Sciences and Social Care, Brunel University London, Uxbridge, United Kingdom.
authors: Mark A
authors: MA
authors: Pook
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D053843:DNA Mismatch Repair; D045643:DNA Repair Enzymes / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D019281:Dimerization; D005621:Friedreich Ataxia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D042822:Genomic Instability; D045325:HCT116 Cells; D006801:Humans; D033862:Iron-Binding Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D014158:Transcription, Genetic; D019680:Trinucleotide Repeat Expansion; D000096923:Frataxin
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D033862:Iron-Binding Proteins; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D009687:Nuclear Proteins; D000096923:Frataxin; C501485:Mlh1 protein, mouse; C500929:MutLalpha protein, human; C499533:Pms2 protein, mouse