RESEARCH ON THE PATHOGENESIS AND PATHOPHYSIOLOGY OF HEREDITARY CERULOPLASMIN DEFICIENCY (ACERULOPLASMINEMIA)

血浆铜蓝蛋白缺乏症是一种由血浆铜蓝蛋白（CP）基因突变引起的常染色体隐性遗传性铁代谢疾病。我们仔细检查了5例患者的大脑与这种疾病的组织病理学和免疫化学。在大脑中，基底神经节（特别是尾状核和壳核）受到的影响最严重，在那里观察到大量的铁沉积和神经元的广泛损失。铁超载在星形胶质细胞中比在神经元中更突出。明显变形的星形胶质细胞和球状体样球状结构被认为是成比例的铁沉积的程度。球状结构清楚地与抗神经胶质细胞酸性蛋白和抗S-100抗体反应，但不与神经元标记蛋白，如神经丝和突触素的抗体反应。因此，它们可能起源于星形胶质细胞。变形的星形胶质细胞和球状结构也对抗4-羟基壬烯醛抗体呈阳性反应。这些发现表明，形态学c ...更多信息 为了阐明CP在铁代谢中的作用，我们制备了CP缺陷（CP^-/->）小鼠。这些小鼠在肝脏中表现出明显的铁过载，以及轻度的小细胞和低色素性贫血，但它们在包括大脑在内的任何其他器官中都没有表现出铁过载。我们用TaqMan RT-PCR检测了十二指肠和肝脏中铁代谢基因的表达水平。CP^<-/->小鼠十二指肠中的二价金属转运蛋白1（DMT 1）、膜铁转运蛋白1（FPN 1）和肝啡肽（HEPH）基因未上调。这一结果与Harris等人先前的铁动力学研究一致，其显示CP^<-/->和CP^<+/+>小鼠之间的肠铁吸收速率没有差异。再加上携带HEPH基因突变的性连锁贫血（SLA）小鼠在十二指肠表现出铁吸收缺陷和严重缺铁性贫血的事实，我们的数据表明CP对肠道铁吸收的重要性低于HEPH。在肝脏中，CP^<-/->小鼠没有显示出DMT 1和转铁蛋白受体（TFR和TFR 2）的基因表达增加，这表明CP^<-/->小鼠的肝细胞中没有激活任何已知的铁摄取途径。这一结果支持了CP主要用于从肝脏细胞中释放铁的假设。少

Aceruloplasminemia is an autosomal recessive disorder of iron metabolism caused by mutations in the ceruloplasmin (CP) gene. We scrutinized the brains of 5 patients with this disease histopathologically and immunohistochemically. In the brain, the basal ganglia (especially the caudate nucleus and putamen) were most severely affected, where heavy iron deposition and extensive loss of neurons were observed. Iron overload was more prominent in astrocytes than in neurons. Markedly deformed astrocytes and spheroid-like globular structures were seen in proportion to the degree of iron deposition. Globular structures clearly reacted with anti-glial fibrillary acidic protein and anti-S-100 antibodies, but not with antibodies for neuronal marker proteins, such as neurofilament and synaptophysin. Therefore, they presumably originated from astrocytes. Deformed astrocytes and globular structures also reacted positively to anti-4-hydroxynonenal antibody. These findings indicate that morphological c … More hanges of astrocytes are closely linked to iron overload and subsequent oxidative stress.In order to elucidate the functional involvement of CP in iron metabolism, we generated CP-deficient (CP^<-/->) mice. The mice showed a marked iron overload in the liver and mild microcytic and hypochromic anemia, but they did not exhibit iron overload in any other organs including the brain. We examined expression levels of the iron-metabolism genes in the duodenum and liver with TaqMan RT-PCR. The divalent metal transporter 1 (DMT1), ferroportin 1 (FPN1), and hephaestin (HEPH) genes were not up-regulated in the duodenum from CP^<-/-> mice. This result is compatible with a previous ferrokinetic study by Harris et al., which showed no difference in the rate of intestinal iron absorption between CP^<-/-> and CP^<+/+> mice. Together with the fact that sex-linked anemia (sla) mice, which carry a mutation in the HEPH gene, show defective iron absorption in the duodenum and severe iron deficiency anemia, our data suggest that CP is less important than HEPH for intestinal iron absorption. In the liver, CP^<-/-> mice showed no increase of gene expression for DMT1 and transferrin receptors (TFR and TFR2), suggesting that any known pathway of iron uptake is not activated in hepatocytes in CP^<-/-> mice. This result supports the hypothesis that CP mainly acts to release iron from cells in the liver. Less