Nature Genetics
28, 350 - 354 (2001)
Published online: 2 July 2001; | doi:10.1038/ng571
Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia diseaseAndrew R.J. Curtis1, Constanze Fey1, Christopher M Morris2, Laurence A. Bindoff3, Paul G. Ince2, Patrick F. Chinnery3, Alan Coulthard3, Margaret J. Jackson3, Andrew P. Jackson4, Duncan P. McHale4, David Hay1, William A. Barker1, Alex F. Markham4, David Bates3, Ann Curtis1
& John Burn51
Institute of Human Genetics, 19/20 Claremont Place, Newcastle upon Tyne, NE2 4AA, UK. 2
Joint MRC-Newcastle University Centre for Development in Clinical Brain Ageing, Newcastle General Hospital, Newcastle upon Tyne, UK. 3
Departments of Neurology, Neuropathology & Radiology, Newcastle Hospitals NHS Trust, Newcastle upon Tyne, UK. 4
Molecular Medicine Unit, Clinical Sciences Building, St. James's University Hospital, Leeds, UK. 5
Present address: Institute of Neurology, University of Bergen, Haukeland Sykehus, 5021 Bergen, Norway.
Correspondence should be addressed to John Burn john.burn@newcastle.ac.ukWe 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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