Cubn-flox Mouse

CUBN, encoding cubilin, is an important gene. Cubilin is an endocytic receptor highly expressed in renal proximal tubules, mediating the uptake of albumin, transferrin, and α1-microglobulin. It also serves as the intestinal receptor for the endocytosis of intrinsic factor-vitamin B12. Mutations in CUBN are associated with Imerslund-Gräsbeck syndrome (IGS), which is characterized by intestinal malabsorption of vitamin B12 and in some cases proteinuria [1,2,4,6].

Research has identified CUBN variants associated with various conditions. Biallelic pathogenic variants in the CUBN gene were associated with chronic isolated proteinuria and early childhood onset, with normal renal function. These proteinuria cases often had a high proportion of albuminuria, and unlike more N-terminal IGS mutations, many proteinuria-associated CUBN variants led to modifications or truncations after the vitamin B12-binding domain [1]. Some studies also found that CUBN gene mutations may cause isolated proteinuria pathologically presented as focal segmental glomerulosclerosis (FSGS) in children [2]. Novel variants after the vitamin B12-binding domain of CUBN were shown to disrupt the association with Amnionless (AMN), causing albuminuria without progressive glomerular filtration barrier impairment [3]. In addition, some CUBN missense variants were associated with higher levels of estimated glomerular filtration rate (eGFR) in non-diabetes populations [5].

In conclusion, CUBN plays a crucial role in renal albumin reabsorption and vitamin B12 uptake. Research on CUBN variants has provided insights into the complex relationship between proteinuria and renal function. Understanding the function of CUBN through these genetic findings helps in clarifying the mechanisms underlying certain kidney-related and vitamin B12-metabolism-related disorders.