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Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease

Nature Genetics volume 28, pages 350–354 (2001)Cite this article

Abstract

We describe here a previously unknown, dominantly inherited, late-onset basal ganglia disease, variably presenting with extrapyramidal features similar to those of Huntington's disease (HD) or parkinsonism. We mapped the disorder, by linkage analysis, to 19q13.3, which contains the gene for ferritin light polypeptide (FTL). We found an adenine insertion at position 460–461 that is predicted to alter carboxy-terminal residues of the gene product. Brain histochemistry disclosed abnormal aggregates of ferritin and iron. Low serum ferritin levels also characterized patients. Ferritin, the main iron storage protein, is composed of 24 subunits of two types (heavy, H and light, L) which form a soluble, hollow sphere1. Brain iron deposition increases normally with age, especially in the basal ganglia, and is a suspected causative factor in several neurodegenerative diseases2 in which it correlates with visible pathology3, possibly by its involvement in toxic free-radical reactions4. We found the same mutation in five apparently unrelated subjects with similar extrapyramidal symptoms. An abnormality in ferritin strongly indicates a primary function for iron in the pathogenesis of this new disease, for which we propose the name 'neuroferritinopathy'.

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Figure 1: Pedigree and linkage analysis.
Figure 2: MRI scan and brain pathology.
Figure 3: Sequence of FTL exon 4 mutation and predicted change in protein.
Figure 4: Inheritance of altered EcoNI restriction digestion and RT-PCR.
Figure 5: Sections of the globus pallidus showing deposits of iron (a) and ferritin (b) in the neuropil adjacent to a cystic lesion (upper left).

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Acknowledgements

We thank the family for their support over many years, K. Archibald of the Northern Genetics Service for doing disease-specific tests, the North Cumbria Community Genetics Project and Westlakes Research Institute for access to control DNA samples and the Cumbria County Records Office for genealogical research. The work is supported by the Borwick Trust and the Royal Victoria Infirmary Special Trustees. C.M.M. and A.P.J. are supported by the Medical Research Council. The paper is dedicated to the late D. Gibson, our genetic nurse, who devoted many hours to the care of this family and tracing of the pedigree.

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  1. John Burn

    Present address: Institute of Neurology, University of Bergen, Haukeland Sykehus, 5021, Bergen, Norway

Authors and Affiliations

  1. Institute of Human Genetics, 19/20 Claremont Place, Newcastle upon Tyne, NE2 4AA, UK

    Andrew R.J. Curtis, Constanze Fey, David Hay, William A. Barker & Ann Curtis

  2. Joint MRC-Newcastle University Centre for Development in Clinical Brain Ageing, Newcastle General Hospital, Newcastle upon Tyne, UK

    Christopher M Morris & Paul G. Ince

  3. Departments of Neurology, Neuropathology & Radiology, Newcastle Hospitals NHS Trust, Newcastle upon Tyne, UK

    Laurence A. Bindoff, Patrick F. Chinnery, Alan Coulthard, Margaret J. Jackson & David Bates

  4. Molecular Medicine Unit, Clinical Sciences Building, St. James's University Hospital, Leeds, UK

    Andrew P. Jackson, Duncan P. McHale & Alex F. Markham

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Correspondence to John Burn.

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Curtis, A., Fey, C., Morris, C. et al. Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat Genet 28, 350–354 (2001). https://doi.org/10.1038/ng571

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