Clinical and Genetic Insights Into Isolated Proteinuria With CUBN Variants.

Area of Science:

• Nephrology
• Genetics
• Molecular Biology

Background:

• Cubilin (CUBN) is vital for vitamin B12 absorption and protein reabsorption.
• Biallelic CUBN variants cause Imerslund-Gräsbeck syndrome (IGS) with proteinuria.
• C-terminal CUBN variants are linked to autosomal recessive chronic benign proteinuria.

Purpose of the Study:

• To investigate the genetic and clinical features of chronic benign proteinuria.
• To elucidate the molecular basis differentiating chronic benign proteinuria from IGS.

Main Methods:

• Targeted panel sequencing in patients with proteinuria and CUBN variants.
• Analysis of clinical characteristics and kidney pathology.
• Identification and characterization of CUBN transcripts and protein isoforms.

Main Results:

• Forty CUBN variants, including 30 novel ones, were found in 52 patients from 42 families.
• Patients presented with subclinical proteinuria and minor glomerular abnormalities.
• A novel CUBN transcript producing a truncated protein with a unique C-terminus was identified.

Conclusions:

• Biallelic CUBN variants in patients lead to preserved kidney function despite glomerular changes.
• C-terminal CUBN variants do not impact vitamin B12 absorption due to specific isoform expression in the intestine.
• This explains the absence of malabsorption in chronic benign proteinuria linked to CUBN C-terminal variants.