Novel pathogenic variants in CUBN uncouple proteinuria from renal function

Area of Science:

• Genetics and Molecular Biology
• Nephrology
• Biochemistry

Background:

• Proteinuria is a risk factor for kidney and cardiovascular disease in chronic kidney disease (CKD).
• The role of all proteinuria types in renal impairment is not fully understood.
• Cubilin is a key endocytic receptor in renal proximal tubules for albumin, transferrin, and α1-microglobulin uptake.

Purpose of the Study:

• To investigate novel genetic variants affecting the Cubilin (CUBN) protein.
• To determine the functional consequences of these variants on kidney function and proteinuria.
• To clarify the relationship between specific proteinuria types and glomerular filtration barrier integrity.

Main Methods:

• Exome and Sanger sequencing to identify candidate genes and variants.
• Bioinformatics analysis to focus on the CUBN gene.
• In vitro (HEK293T cells) and in vivo (mice) experiments to assess variant expression and function.
• Clinical data analysis of affected families.

Main Results:

• Four novel CUBN variants were identified in two families, located after the vitamin B12-binding domain.
• These variants impaired Cubilin expression and function, leading to increased urinary albumin, transferrin, and α1-microglobulin.
• Importantly, no progressive glomerular filtration barrier impairment, vitamin B12 deficiency, or abnormal blood lipid/albumin levels were observed.

Conclusions:

• Mutations in CUBN after the vitamin B12-binding domain can uncouple proteinuria from glomerular filtration barrier damage.
• This suggests a potentially common, benign form of proteinuria in humans.
• Such cases may not necessitate proteinuria-lowering treatments or renal biopsy.