Defective CUBN does not transport GIF:Cbl

In preparation for internalisation, the gastric intrinsic factor:cobalamin (GIF:Cbl) complex interacts with the cubilin:protein amnionless complex (CUBN:AMN). CUBN is a cotransporter facilitating uptake of lipoproteins, vitamins and iron. Protein amnionless (AMN) is a necessary component which directs subcellular localization and endocytosis of GIF:Cbl.<br><br>Defects in CUBN cause recessive hereditary megaloblastic anemia 1 (RH-MGA1 aka MGA1 Finnish type or Imerslund-Grasbeck syndrome, I-GS; MIM:261100). The Finnish cases described by Grasbeck et al. were caused by defects in CUBN whereas the Norwegian cases described by Imerslund were due to defects in AMN (Grasbeck et al. 1960, Imerslund 1960 respectively). The resultant malabsorption of Cbl (vitamin B12) leads to impaired B12-dependent folate metabolism and ultimately impaired thymine synthesis and DNA replication. Cells involved in erythropoiesis are particularly affected. MGA1 occurs worldwide, but its prevalence is higher in several Middle Eastern countries, in Norway and highest in Finland (0.8 in 100,000). The P1297L mutation in CUBN is most commonly found in Finland (Aminoff et al. 1999, Kristiansen et al. 2000).

为促进国际化，胃内因子：钴胺素（GIF:Cbl）复合物与立方素：无羊膜蛋白复合物（CUBN:AMN）相互作用。CUBN是一种共转运蛋白，有助于脂蛋白、维生素和铁的摄取。无羊膜蛋白（AMN）是该复合体的必要组成部分，它指导GIF:Cbl在亚细胞中的定位和内吞作用。<br><br>CUBN基因的缺陷导致隐性遗传性巨幼细胞性贫血1（RH-MGA1，亦称芬兰型MGA1或Imerslund-Grasbeck综合征，I-GS；MIM:261100）。Grasbeck等人在1960年描述的芬兰病例是由CUBN基因缺陷引起的，而Imerslund在1960年描述的挪威病例则是由AMN基因缺陷所致。Cbl（维生素B12）吸收不良导致维生素B12依赖性叶酸代谢受损，进而影响胸腺嘧啶合成和DNA复制。红细胞生成过程中涉及的细胞尤为敏感。MGA1在全球范围内均有发生，但其发病率在几个中东国家、挪威以及芬兰最高（芬兰的发病率为10万分之一0.8）。CUBN中的P1297L突变在芬兰最为常见（Aminoff等，1999；Kristiansen等，2000）。