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A novel deletion–insertion mutation identified in exon 3 of FXN in two siblings with a severe Friedreich ataxia phenotype

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Abstract

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease most commonly caused by a GAA trinucleotide repeat expansion in the first intron of FXN, which reduces expression of the mitochondrial protein frataxin. Approximately 98% of individuals with FRDA are homozygous for GAA expansions, with the remaining 2% compound heterozygotes for a GAA expansion and a point mutation within FXN. Two siblings with early onset of symptoms experienced rapid loss of ambulation by 8 and 10 years. Diagnostic testing for FRDA demonstrated one GAA repeat expansion of 1010 repeats and one non-expanded allele. Sequencing all five exons of FXN identified a novel deletion-insertion mutation in exon 3 (c.371_376del6ins15), which results in a modified frataxin protein sequence at amino acid positions 124–127. Specifically, the amino acid sequence changes from DVSF to VHLEDT, increasing frataxin from 211 residues to 214. Using the known structure of human frataxin, a theoretical 3D model of the mutant protein was developed. In the event that the modified protein is expressed and stable, it is predicted that the acidic interface of frataxin, known to be involved in iron binding and interactions with the iron–sulphur cluster assembly factor IscU, would be impaired.

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Acknowledgements

The authors would like to sincerely thank the participating family as well as Gabrielle Wilson and Paul Lockhart for their assistance. This study was supported by funding from the Friedreich Ataxia Research Alliance, USA, the Friedreich Ataxia Research Association, Australasia, the Australian Rotary Health Research Fund, the North Brighton Rotary Club, the Collier Charitable Fund of Australia and the Victorian Government Operational Infrastructure Support Program. MBD is a National Health and Medical Research Council of Australia Practitioner Fellow.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Flemington Road, Parkville, Victoria, 3052, Australia

    Marguerite V. Evans-Galea, Louise A. Corben, Michael C. Fahey & Martin B. Delatycki

  2. Department of Paediatrics, The University of Melbourne, Royal Children’s Hospital, Parkville, Victoria, 3052, Australia

    Marguerite V. Evans-Galea & Martin B. Delatycki

  3. Experimental Neuropsychology Research Unit, School of Psychology, Psychiatry and Psychological Medicine, Monash University, Clayton, Victoria, 3168, Australia

    Louise A. Corben

  4. Molecular Genetics Laboratory, Victorian Clinical Genetics Services Pathology, Murdoch Childrens Research Institute, Parkville, Victoria, 3052, Australia

    Justin Hasell & Desirée du Sart

  5. Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, 3052, Australia

    Charles A. Galea

  6. Monash Neurology, Monash Medical Centre, Clayton, Victoria, 3168, Australia

    Michael C. Fahey & Martin B. Delatycki

  7. Department of Paediatrics, Monash University, Clayton, Victoria, 3168, Australia

    Michael C. Fahey

  8. Clinical Genetics, Austin Health, Heidelberg West, Victoria, 3081, Australia

    Martin B. Delatycki

Authors
  1. Marguerite V. Evans-Galea
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  2. Louise A. Corben
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  3. Justin Hasell
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  4. Charles A. Galea
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  5. Michael C. Fahey
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  6. Desirée du Sart
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  7. Martin B. Delatycki
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Corresponding author

Correspondence to Martin B. Delatycki.

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Supplementary Fig. 1

Multiple amino acid sequence alignment of frataxin from various species. The alignment was performed using ClustalW2 on the Protein Information Resource (PRI) website (http://pir.georgetown.edu/pirwww/index.shtml). Amino acid residues known to bind iron are coloured red while residues involved in binding to IscU are blue and those that bind to both iron and IscU are green [36]. The site of the deletion–insertion mutation is in bold. (JPEG 213 kb)

High Resolution Image (TIFF 1190 kb)

Supplementary Fig. 2

Amino acid sequence alignment of the yeast and human Fe-S cluster scaffold proteins Isu1p and IscU. The alignment was performed using Clustal W2 on the Protein Information Resource (PRI) website (http://pir.georgetown.edu/pirwww/index.shtml). (JPEG 37 kb)

High Resolution Image (TIFF 361 kb)

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Evans-Galea, M.V., Corben, L.A., Hasell, J. et al. A novel deletion–insertion mutation identified in exon 3 of FXN in two siblings with a severe Friedreich ataxia phenotype. Neurogenetics 12, 307–313 (2011). https://doi.org/10.1007/s10048-011-0296-3

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  • DOI: https://doi.org/10.1007/s10048-011-0296-3

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