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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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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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)
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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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DOI: https://doi.org/10.1038/ng1826
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