Hereditary Ferritinopathy: A Novel Mutation, Its Cellular Pathology, and Pathogenetic Insights

Division of General Medicine, University of Rochester, Rochester, New York, United States
Journal of Neuropathology and Experimental Neurology (Impact Factor: 3.8). 05/2005; 64(4):280-94. DOI: 10.1093/jnen/64.4.280
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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    • "The cause is usually a frameshift mutation in exon 4 for the L-ferritin gene, which causes a conformational change in the C-terminus of the molecule and alters its ability to store iron [35,36]. The mutation results in iron/ferritin-rich aggregates forming in cells [37]. Mouse transgenic models show a strong relation between functional changes and abnormal iron metabolism [38]. "
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    ABSTRACT: Iron is a trace element of considerable interest to both chemistry and biology. In a biological context its chemistry is vital to the roles it performs. However, that same chemistry can contribute to a more deleterious role in a variety of diseases. The brain is a very sensitive organ due to the irreplaceable nature of neurons. In this regard regulation of brain iron chemistry is essential to maintaining neuronal viability. During the course of normal aging, the brain changes the way it deals with iron and this can contribute to its susceptibility to disease. Additionally, many of the known neurodegenerative diseases have been shown to be influenced by changes in brain iron. This review examines the role of iron in the brain and neurodegenerative diseases and the potential role of changes in brain iron caused by aging.
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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.
    Full-text · Article · Mar 2015 · Neurobiology of Disease
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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.
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