FXN methylation predicts expression and clinical outcome in Friedreich ataxia

Authors

  • Marguerite V. Evans-Galea PhD,

    Corresponding author
    1. Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
    2. Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
    • Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Flemington Road, Parkville VIC 3052, Australia
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  • Nissa Carrodus,

    1. Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
    Current affiliation:
    1. Ms Carrodus: Brain Development, Florey Neuroscience Institutes, Parkville, Victoria, Australia
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  • Simone M. Rowley,

    1. Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
    Current affiliation:
    1. Ms Rowley: Victorian Breast Cancer Research Consortium, Cancer Genetics, Peter MacCallum Cancer Centre, Victoria, Australia
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  • Louise A. Corben PhD,

    1. Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
    2. Experimental Neuropsychology Research Unit, School of Psychology, Psychiatry, School of Psychology and Psychiatry, Monash University, Clayton, Victoria, Australia
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  • Geneieve Tai,

    1. Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
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  • Richard Saffery PhD,

    1. Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
    2. Cancer, Disease, and Developmental Epigenetics, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
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  • John C. Galati PhD,

    1. Clinical Epidemiology and Biostatistics Unit, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
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  • Nicholas C. Wong PhD,

    1. Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
    2. Cancer, Disease, and Developmental Epigenetics, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
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  • Jeffrey M. Craig PhD,

    1. Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
    2. Early Life Epigenetics, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
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  • David R. Lynch MD, PhD,

    1. Departments of Neurology and Pediatrics, University of Pennsylvania School of Medicine and Childrens Hospital of Philadelphia, Philadelphia, PA
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  • Sean R. Regner,

    1. Departments of Neurology and Pediatrics, University of Pennsylvania School of Medicine and Childrens Hospital of Philadelphia, Philadelphia, PA
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  • Alicia F. D. Brocht,

    1. Clinical Trials Coordination Center in the Center for Human Experimental Therapeutics, University or Rochester, Rochester, NY
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  • Susan L. Perlman MD,

    1. Ataxia Center and Huntington Disease Center of Excellence, Department of Neurology, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA
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  • Khalaf O. Bushara MD, FRCP,

    1. Ataxia Center, University of Minnesota, Minneapolis, MN
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  • Christopher M. Gomez MD, PhD,

    1. Department of Neurology, University of Chicago Medical Center, Chicago, IL
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  • George R. Wilmot MD, PhD,

    1. Department of Neurology, Emory University School of Medicine, Atlanta, GA
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  • Lingli Li,

    1. Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
    Current affiliation:
    1. Ms Li: Australian Centre for Blood Diseases, Central Medical School, Monash University Department of Haematology, Alfred Hospital, Prahran, Victoria, Australia
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  • Elizabeth Varley,

    1. Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
    2. Centre for Community Child Health, Healthy Development, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
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  • Martin B. Delatycki MBBS, FRACP, PhD,

    1. Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
    2. Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
    3. Clinical Genetics, Austin Health, Heidelberg, Victoria, Australia
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  • Joseph P. Sarsero PhD

    1. Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
    2. Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
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  • D.R.L., S.L.P., K.O.B., C.M.G., G.R.W., and M.B.D. are members of the Collaborative Clinical Research Network of Friedreich Ataxia (established and supported by the Friedreich Ataxia Research Alliance, USA).

Abstract

Objective:

Friedreich ataxia (FA) is the most common ataxia and results from an expanded GAA repeat in the first intron of FXN. This leads to epigenetic modifications and reduced frataxin. We investigated the relationships between genetic, epigenetic, and clinical parameters in a large case–control study of FA.

Methods:

Clinical data and samples were obtained from individuals with FA during annual visits to our dedicated FA clinic. GAA expansions were evaluated by polymerase chain reaction (PCR) and restriction endonuclease digest. DNA methylation was measured using bisulfite-based EpiTYPER MassARRAY (Sequenom, San Diego, CA). FXN expression was determined using real-time reverse transcriptase PCR. Significant correlations between the different parameters were examined using the nonparametric Spearman rank correlation coefficient, as well as univariate and multivariate regression modeling.

Results:

Characteristic DNA methylation was identified upstream and downstream of the expansion, and validated in an independent FA cohort. Univariate and multivariate analyses showed significant inverse correlations between upstream methylation and FXN expression, and variation in downstream methylation and age of onset. FXN expression also inversely correlated with the Friedreich Ataxia Rating Scale score, an indicator of disease severity.

Interpretation:

These novel findings provide compelling evidence for the link between the GAA expansion, the DNA methylation profile, FXN expression, and clinical outcome in FA. Epigenetic profiling of FXN could be used to gain greater insight into disease onset and progression, but also as a biomarker to learn more about specific treatment responses and pharmacological mechanism(s). This work also highlights the potential for developing therapies aimed at increasing frataxin levels to treat this debilitating disease. ANN NEUROL 2012;

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