Search

Friedreich's ataxia is caused by large homozygous, intronic expansions of GAA repeats in the frataxin (FXN) gene, resulting in severe downregulation of its expression. Pathogenic repeats are located in intron one, hence patients express unaffected FXN protein, albeit in low quantities. Although FRDA symptoms typically afflict the nervous system, hypertrophic cardiomyopathy is the predominant cause of death. Our studies were conducted using cardiomyocytes differentiated from induced pluripotent stem cells derived from control individuals, FRDA patients, and isogenic cells corrected by zinc finger nucleases-mediated excision of pathogenic expanded GAA repeats. This correction of the FXN gene removed the primary trigger of the transcription defect, upregulated frataxin expression, reduced pathological lipid accumulation observed in patient cardiomyocytes, and reversed gene expression signatures of FRDA cardiomyocytes. Transcriptome analyses revealed hypertrophy-specific expression signatures unique to FRDA cardiomyocytes, and emphasized similarities between unaffected and ZFN-corrected FRDA cardiomyocytes. Thus, the iPSC-derived FRDA cardiomyocytes exhibit various molecular defects characteristic for cellular models of cardiomyopathy that can be corrected by genome editing of the expanded GAA repeats. These results underscore the utility of genome editing in generating isogenic cellular models of FRDA and the potential of this approach as a future therapy for this disease., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Friedreich's Ataxia (FRDA) is a very common cause of hereditary autosomal recessive ataxia among western Europeans. We aim to define the frequency of FRDA in Chinese Han population due to the lack of reports of FRDA in China. The GAA trinucleotide repeats in the FXN gene were analyzed by triplet repeat-primed PCR (TP-PCR) in 122 unrelated hereditary ataxia (HA) and 114 unrelated hereditary spastic paraplegia (HSP) patients. The GAA copy numbers in the FXN gene of all the subjects ranged from 5 to 16. There were no FRDA patients that could be diagnosed base on the results of TP-PCR. It suggests that FRDA is a very rare cause of inheritance ataxia and FRDA genetic analysis should not be used as a routine genetic diagnosis test in China., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Reduced expression of the mitochondrial protein Frataxin (FXN) is the underlying cause of Friedreich's ataxia. We propose a model of premature termination of FXN transcription induced by pathogenic expanded GAA repeats that links R-loop structures, antisense transcription, and heterochromatin formation as a novel mechanism of transcriptional repression in Friedreich's ataxia.

Introduction:- Friedreich’s ataxia is anautosomal recessive disease due to a mutationin gene X25. This gene codes for frataxin and itis located on chromosome 9. The disease iscaused by a triplet particular sequence of bases(GAA). Normally, the GAA sequence is repeated 7 to 22 times, but in people with Friedreich’sataxia, it can be repeated hundreds or even overthousand times.Objectives:To determine if there is a correlationbetween clinical and molecular findingsin our FRDA patients.Methods: Eleven patients with the typicalFriedreich´s ataxia phenotype were studied byPCR we determined the size of the GAA expansions,and analyzed the correlation of age at onset andrate of disease progression with the number ofGAA repetitions.Results and conclusions: Molecular analysisby PCR showed eight homozygous patientsfor the expansion and three negative. The averageof the size of the expansions in the allelewas of 622±5 with an average in the age ofbeginning of 13±8. For the sample size, therewas no significant statistical correlation betweenthe age of beginning of the disease and thenumber of repetitions, although there was likean inverse correlation.Besides understanding of FRDA physiology andthe Harding clinical inclusion criteria, moleculardiagnosis is an important step in the achievementof an optimal therapeutic treatment.