Hereditary ferritinopathy: A novel mutation, its cellular pathology, and pathogenetic insights
Hereditary ferritinopathy: A novel mutation, its cellular pathology, and pathogenetic insights
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DOI：
10.1093/jnen/64.4.280
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发表时间：
2005-04-01
影响因子：
3.2
通讯作者：
Powers, JM
中科院分区：
文献类型：
--
作者：
Mancuso, M;Davidzon, G;Powers, JM
我们报告了一个遗传性铁蛋白病(神经性铁蛋白病)的法国、加拿大和荷兰血统的家族，以及铁蛋白轻链基因的一个新的突变(在外显子4的nt646-647处插入C)，导致了比正常蛋白更长的蛋白质。我们未能用铁蛋白轻链的构象依赖的单抗对先证者中的大多数异常铁蛋白沉积进行免疫染色，这支持了先前假设的铁蛋白轻链在本病中的构象变化。后壳核和小脑是我们先证者的主要病理部位，但也存在无症状的肝细胞内铁和铁蛋白聚集。神经元和神经胶质细胞都表现出高度的特异性，即使不是病理性的，也是肿胀到含有恐怖蛋白和铁的空泡化的细胞核。透明质沉积，铁蛋白和铁的染色，是铁素病所特有的额外的形态特征。铁，至少在壳核中有近40倍的增加，似乎同时以亚铁(Fe2+)和铁(Fe3+)的形式存在；它最有可能是观察到的神经元和神经胶质细胞凋亡的原因。我们在壳核神经元和神经胶质细胞中发现了脂质过氧化和蛋白质异常硝化的形态证据，证实了这种过量铁造成的预期氧化应激。线粒体的生化和免疫组织化学异常也被证实，可能是由于铁稳态的失衡对呼吸链产生了有害的影响。
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 territin 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 inuminohisto-chemical abnormalities in mitochondria also were demonstrated, probably due to an imbalance in iron homeostasis that had a deleterious effect on the respiratory chain.