| Autor: |
Nethisinghe S; Ataxia Centre, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK., Kesavan M; Ataxia Centre, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK., Ging H; Ataxia Centre, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK., Labrum R; Neurogenetics Service, Rare and Inherited Disease Laboratory, London North Genomic Laboratory Hub, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3BH, UK., Polke JM; Neurogenetics Service, Rare and Inherited Disease Laboratory, London North Genomic Laboratory Hub, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3BH, UK., Islam S; UCL Queen Square Institute of Neurology, London WC1N 3BG, UK., Garcia-Moreno H; Ataxia Centre, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK., Callaghan MF; Wellcome Centre for Human Neuroimaging, UCL Queen Square Institute of Neurology, University College London, London WC1N 3AR, UK., Cavalcanti F; Institute for Biomedical Research and Innovation (IRIB), Italian National Research Council (CNR), 87050 Mangone, Italy., Pook MA; Ataxia Research Group, Division of Biosciences, Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK.; Synthetic Biology Theme, Institute of Environment, Health and Societies, Brunel University London, Uxbridge UB8 3PH, UK., Giunti P; Ataxia Centre, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK. |
| Abstrakt: |
Friedreich's ataxia (FRDA) is a comparatively rare autosomal recessive neurological disorder primarily caused by the homozygous expansion of a GAA trinucleotide repeat in intron 1 of the FXN gene. The repeat expansion causes gene silencing that results in deficiency of the frataxin protein leading to mitochondrial dysfunction, oxidative stress and cell death. The GAA repeat tract in some cases may be impure with sequence variations called interruptions. It has previously been observed that large interruptions of the GAA repeat tract, determined by abnormal Mbo II digestion, are very rare. Here we have used triplet repeat primed PCR (TP PCR) assays to identify small interruptions at the 5' and 3' ends of the GAA repeat tract through alterations in the electropherogram trace signal. We found that contrary to large interruptions, small interruptions are more common, with 3' interruptions being most frequent. Based on detection of interruptions by TP PCR assay, the patient cohort ( n = 101) was stratified into four groups: 5' interruption, 3' interruption, both 5' and 3' interruptions or lacking interruption. Those patients with 3' interruptions were associated with shorter GAA1 repeat tracts and later ages at disease onset. The age at disease onset was modelled by a group-specific exponential decay model. Based on this modelling, a 3' interruption is predicted to delay disease onset by approximately 9 years relative to those lacking 5' and 3' interruptions. This highlights the key role of interruptions at the 3' end of the GAA repeat tract in modulating the disease phenotype and its impact on prognosis for the patient. |
