Hereditary ferritinopathy: A novel mutation, its cellular pathology, and pathogenetic insights

Department of Neurology, Columbia College of Physicians & Surgeons, New York, New York, USA.
Journal of Neuropathology and Experimental Neurology (Impact Factor: 3.8). 05/2005; 64(4):280-94.
Source: PubMed


We report a family of French Canadian and Dutch ancestry with hereditary ferritinopathy (neuroferritinopathy) and a novel mutation (C insertion at nt646-647 in exon 4) in the ferritin light chain gene, resulting in a longer than normal protein. Our failure to immunostain most of the abnormal ferritin deposits in the proband with a conformation-dependent monoclonal antibody to ferritin light chain supported a previously postulated conformational change of ferritin light chain in this disease. The posterior putamen and cerebellum were the primary pathologic loci in our proband, but asymptomatic hepatocytic intranuclear accumulations of iron and ferritin also were present. Both neurons and glia displayed highly distinctive, if not pathognomonic, swollen to vacuolated nuclei containing ferritin and iron. Hyaline deposits, again staining for both ferritin and iron, were additional morphologic features that may be unique to the ferritinopathies. The iron, at least in putamen where there was a nearly 40-fold increase, appeared to be both in the ferrous (Fe2+) and ferric (Fe3+) form; it was the most likely cause of the observed neuronal and glial apoptosis. We found morphologic evidence of both lipid peroxidation and abnormal nitration of proteins in putaminal neurons and glia, confirming the expected oxidative stress due to this excessive iron. Biochemical and immunohistochemical abnormalities in mitochondria also were demonstrated, probably due to an imbalance in iron homeostasis that had a deleterious effect on the respiratory chain.

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    • "However, it should be taken into account that the iron/ferritin aggregates can be present in brain patients several years before the developing of symptoms, as revealed by MRI analysis (Keogh et al., 2012). In addition, they are present in extraneuronal tissues that do not always show dysfunction (Curtis et al., 2001; Mancuso et al., 2005). "
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    ABSTRACT: Neuroferritinopathy is a rare, late-onset, dominantly inherited movement disorder caused by mutations in L-ferritin gene. It is characterized by iron and ferritin aggregates accumulation in brain, normal or low serum ferritin levels and high variable clinical feature. To date, nine causative mutations have been identified and eight of them are frameshift mutations determined by nucleotide(s) insertion in the exon 4 of L-ferritin gene altering the structural conformation of the C-terminus of the L-ferritin subunit. Acting in a dominant negative manner, mutations are responsible for an impairment of the iron storage efficiency of ferritin molecule. Here, we review the main characteristics of neuroferritinopathy and present a computational analysis of some representative recently defined mutations with the purpose to gain new information about the pathogenetic mechanism of the disorder. This is particularly important as neuroferritinopathy can be considered an interesting model to study the relationship between iron, oxidative stress and neurodegeneration. Copyright © 2015. Published by Elsevier Inc.
    Neurobiology of Disease 03/2015; 1800. DOI:10.1016/j.nbd.2015.02.007 · 5.08 Impact Factor
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    • "Superoxide dismutase 1 (SOD1), an ROS scavenger, remained unchanged for the Lwt clone grown for up to 14 days, while it increased to comparable levels in the two variant clones, possibly as a response to oxidative stress (Fig. 1F). L-ferritin variant expression induces apoptosis in HeLa cells There is in vivo morphological evidence for oxidative damage to neurons and glia in the putamen of a patient with the 498InsTC mutation (Mancuso et al., 2005); therefore, we analyzed the relationship between oxidative stress and cellular death. After 4 days of growth in the absence of doxycycline, we could not detect signs of apoptosis or cell death, but after 10–14 days analysis, the fluorescent dye 4,6-diamidino-z-phenylindole (DAPI) showed about 10–15% apoptotic cells for the 460InsA clone and 20% for the 498InsTC clone, while it showed b 2% for the Lwt clone (Fig. 2A). "
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    ABSTRACT: Neuroferritinopathy is a rare genetic disease with a dominant autosomal transmission caused by mutations of the ferritin light chain gene (FTL). It belongs to Neurodegeneration with Brain Iron Accumulation, a group of disorders where iron dysregulation is tightly associated with neurodegeneration. We studied the 498–499InsTC mutation which causes the substitution of the last 9 amino acids and an elongation of extra 16 amino acids at the C-terminus of L-ferritin peptide. An analysis with cyclic voltammetry on the purified protein showed that this structural modification severely reduces the ability of the protein to store iron. In order to analyze the impact of the mutation in vivo, we generated mouse models for the some pathogenic human FTL gene in FVB and C57BL/6J strains.
    Neurobiology of Disease 11/2014; DOI:10.1016/j.nbd.2014.10.023 · 5.08 Impact Factor
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    • "Conversely, too much iron can also cause neurologic disease. Neuroferritinopathy, a disorder of movement characterized by extrapyramidal symptoms, is thought to be because of a mutation in ferritin light chain gene 1 resulting in ferritin and iron accumulation in the brain (Mancuso et al., 2005). "
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    ABSTRACT: Iron is essential for normal cellular functioning of the central nervous system. Abnormalities in iron metabolism may lead to neuronal death and abnormal iron deposition in the brain. Several studies have suggested a link between brain iron deposition in normal aging and chronic neurologic diseases, including multiple sclerosis (MS). In MS, it is still not clear whether iron deposition is an epiphenomenon or a mediator of disease processes. In this review, the role of iron in the pathophysiology of MS will be summarized. In addition, the importance of conventional and advanced magnetic resonance imaging techniques in the characterization of brain iron deposition in MS will be reviewed. Although there is currently not enough evidence to support clinical use of iron chelation in MS, an overview of studies of iron chelation or antioxidant therapies will be also provided.
    Neurobiology of Aging 05/2014; 35. DOI:10.1016/j.neurobiolaging.2014.03.039 · 5.01 Impact Factor
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