CUBN Gene (Cubilin): Function, Associated Diseases, and Mutations

The CUBN gene encodes cubilin, a large endocytic receptor protein primarily expressed in the renal proximal tubule and intestinal epithelium. Cubilin plays a critical role in the reabsorption of albumin and other filtered proteins in the kidney, and in the intestinal absorption of vitamin B12 (cobalamin) in complex with intrinsic factor. It is a peripheral membrane protein that requires the co-receptor amnionless (AMN) for membrane attachment and internalization. Mutations in CUBN are associated with Imerslund-Gräsbeck syndrome (a form of hereditary megaloblastic anemia) and have been linked to chronic kidney disease and albuminuria.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Vitamin B12 absorption and transport

• Receptor-mediated endocytosis in renal proximal tubule

• Protein reabsorption in kidney

Cubilin is a 460 kDa peripheral membrane glycoprotein with a large extracellular domain containing 27 CUB domains, which mediate ligand binding. It lacks a transmembrane domain and relies on interaction with amnionless (AMN) for membrane anchoring and endocytosis. Cubilin binds to intrinsic factor-vitamin B12 complex in the intestine and to albumin, transferrin, and other proteins in the renal tubule. It is essential for vitamin B12 homeostasis and protein reabsorption, and its dysfunction leads to clinical phenotypes such as megaloblastic anemia and proteinuria.