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PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron

Nature Genetics volume 38, pages 752–754 (2006)Cite this article

A Corrigendum to this article was published on 01 August 2006

This article has been updated

Abstract

Neurodegenerative disorders with high brain iron include Parkinson disease, Alzheimer disease and several childhood genetic disorders categorized as neuroaxonal dystrophies. We mapped a locus for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA) to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a calcium-independent group VI phospholipase A2, in NBIA, INAD and the related Karak syndrome. This discovery implicates phospholipases in the pathogenesis of neurodegenerative disorders with iron dyshomeostasis.

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Figure 1: Schematic showing iPLA2-VIA protein structure7 and mutation-derived changes.

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Change history

  • 17 July 2006

    In the version of this article initially published, the authors neglected to acknowledge sample contributions. Samples were obtained from the "Cell line and DNA bank from patients affected by genetic diseases" collection at the Giannina Gaslini Institute (http://www.gaslini.org/labdppm.htm) supported by Italian Telethon grants (project #GTF04002). This error has been corrected in the PDF version of the article.

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Acknowledgements

We are grateful to the many contributing individuals, families and physicians. This work was funded by the Wellcome Trust and WellChild (E.M.), by the US National Eye Institute, L'Association Internationale De Dystrophie Neuro Axonale Infantile, the US National Institute of Child Health and Human Development, and the R.J. Murdock Foundation (S.J.H.) and by the NBIA Disorders Association and NORD (E.M., S.J.H.). Additional support was provided by the Paolo Zorzi Foundation, the Italian National Ministry of Health and the Oregon Alzheimer Disease Center Grant (P30 AG008017). Genotyping services were provided by the CIDR through a federal contract from the US NIH to The Johns Hopkins University, contract number N01-HG-65403 and by the OHSU GCRC (grant M01 RR000334). We thank H. Consencgo for technical assistance. J.G. is an investigator with the Howard Hughes Medical Institute.

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Author notes

  1. Neil V Morgan and Shawn K Westaway: These individuals contributed equally to this work.

Authors and Affiliations

  1. Section of Medical & Molecular Genetics, University of Birmingham School of Medicine, Edgbaston, Birmingham, B15 2TT, UK

    Neil V Morgan, Paul Gissen, Hakan Cangul, Shanaz Pasha, Colin A Johnson & Eamonn R Maher

  2. Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, 97239, Oregon, USA

    Shawn K Westaway, Allison Gregory, Scott Sonek, Jason Coryell, Beth Wilmot, Patricia Kramer & Susan J Hayflick

  3. West Midlands Regional Genetics Service, Birmingham Women's Hospital, Birmingham, B15 2TG, UK

    Jenny E V Morton, Natalie Canham & Eamonn R Maher

  4. Department of Medical Genetics, Uludag University School of Medicine, Bursa, 16036, Turkey

    Hakan Cangul

  5. Department of Child Neurology, Istituto Nazionale Neurologico “Carlo Besta”, Milan, 20133, Italy

    Nardo Nardocci & Giovanna Zorzi

  6. Department of Pediatric Neurology, Hôpital Armand Trousseau, Paris, 75571, France

    Diana Rodriguez

  7. Department of Pediatric Neurology, Hôpital Necker Enfants Malades, Paris, 75270, France

    Isabelle Desguerre

  8. Neurology Department, King Hussein Medical Centre, Amman, 11947, Jordan

    Amar Mubaidin

  9. Unit of Molecular Medicine, Bambino Gesù Hospital, Rome, 00165, Italy

    Enrico Bertini

  10. Division of Genetics and Molecular Medicine, Kings College London School of Medicine, Guys Hospital, London, SE1 9RT, UK

    Richard C Trembath

  11. Department of Neurological and Visual Sciences, University of Verona School of Medicine, Verona, 37129, Italy

    Alessandro Simonati

  12. Nemours Research Programs, A.I. duPont Hospital for Children, Wilmington, 19899, Delaware, USA

    Carolyn Schanen

  13. Department of Medicine, University of California, San Francisco, 94143, California, USA

    Barbara Levinson & Jane Gitschier

  14. Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 1TN, UK

    C Geoffrey Woods

  15. Department of Neurology, Oregon Health & Science University, Portland, 97239, Oregon, USA

    Patricia Kramer & Susan J Hayflick

  16. Howard Hughes Medical Institute, Oregon Health & Science University, Portland, 97239, Oregon, USA

    Jane Gitschier

  17. Department of Pediatrics, Oregon Health & Science University, Portland, 97239, Oregon, USA

    Susan J Hayflick

Authors
  1. Neil V Morgan
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  2. Shawn K Westaway
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  3. Jenny E V Morton
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  4. Allison Gregory
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  7. Hakan Cangul
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  8. Jason Coryell
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  9. Natalie Canham
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  16. Enrico Bertini
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  17. Richard C Trembath
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  18. Alessandro Simonati
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  19. Carolyn Schanen
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  20. Colin A Johnson
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  21. Barbara Levinson
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  22. C Geoffrey Woods
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  23. Beth Wilmot
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  24. Patricia Kramer
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  26. Eamonn R Maher
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  27. Susan J Hayflick
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Corresponding author

Correspondence to Susan J Hayflick.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Pedigree and genotypes of NBIA index family. (PDF 101 kb)

Supplementary Fig. 2

INAD1 locus candidate region. (PDF 142 kb)

Supplementary Fig. 3

PLA2G6 genomic organization and index patient mutations. (PDF 85 kb)

Supplementary Fig. 4

Brain MRI of individual with NBIA. (PDF 92 kb)

Supplementary Table 1

Primer sequences. (PDF 62 kb)

Supplementary Methods (PDF 98 kb)

Supplementary Note (PDF 74 kb)

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Morgan, N., Westaway, S., Morton, J. et al. PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Nat Genet 38, 752–754 (2006). https://doi.org/10.1038/ng1826

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