Article

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

ABSTRACT

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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    • "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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    • "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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