Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function.

Area of Science:

• Genetics and Molecular Biology
• Nephrology
• Biochemistry

Background:

• Proteinuria is a marker of kidney and cardiovascular disease, but its damaging potential varies.
• Mutations in the CUBN gene cause Imerslund-Gräsbeck syndrome (IGS), affecting vitamin B12 absorption and sometimes causing proteinuria.
• CUBN encodes cubilin, a receptor involved in intestinal and renal uptake.

Purpose of the Study:

• To investigate the role of CUBN variants in hereditary renal disease and chronic proteinuria.
• To determine if specific CUBN mutations are associated with benign albuminuria.
• To clarify the function of cubilin's C-terminal domain in renal albumin reabsorption.

Main Methods:

• Next-generation sequencing of renal disease genes in patients with suspected hereditary renal disease and chronic proteinuria.
• Bioinformatic, structural modeling, and epidemiological analyses of identified CUBN variants.
• Meta-analyses of large population-based cohorts to assess the impact of C-terminal CUBN variants.

Main Results:

• Biallelic pathogenic CUBN variants were identified in 39 patients with chronic isolated proteinuria and early childhood onset.
• These patients exhibited normal renal function, and their proteinuria was often misdiagnosed as glomerular diseases.
• C-terminal CUBN variants were associated with albuminuria and a slight increase in glomerular filtration rate (GFR) in population studies.

Conclusions:

• The C-terminal half of cubilin plays a crucial role in renal albumin reabsorption.
• Albuminuria resulting from reduced cubilin function may represent a common, benign human condition.
• This benign albuminuria may not necessitate proteinuria-lowering treatments or renal biopsies.