Clinical and Genetic Insights Into Isolated Proteinuria With CUBN Variants

Cubilin is a multiligand receptor essential for vitamin B12 uptake in the small intestine and for low-molecular-weight protein reabsorption in the proximal tubule. Biallelic CUBN variants cause Imerslund-Gräsbeck syndrome (IGS), often accompanied by proteinuria, whereas C-terminal variants have been associated with autosomal recessive chronic benign proteinuria. This study aimed to clarify the genetic and clinical characteristics of chronic benign proteinuria and the molecular basis distinguishing it from IGS.

We evaluated patients with proteinuria carrying biallelic CUBN variants identified through targeted panel sequencing and investigated molecular mechanisms underlying the phenotypic differences between IGS and chronic benign proteinuria.

Fifty-two patients from 42 families were analyzed, and 40 CUBN variants, including 30 novel variants, were identified. All patients presented with incidentally detected subclinical proteinuria-most commonly during the 3-year-old mass urinary screening-and none showed hypoalbuminemia, impaired kidney function, or response to renin-angiotensin system (RAS) inhibitors. Light microscopy revealed minor glomerular abnormalities, whereas electron microscopy frequently demonstrated thin basement membranes or mild foot process effacement. We identified a novel CUBN transcript containing an open reading frame that produces a truncated protein with a unique C-terminus. Full-length cubilin was expressed only in the kidney, whereas a smaller isoform was present in both kidney and small intestine.

Patients with biallelic CUBN variants exhibit preserved kidney function despite subtle glomerular changes. Because only the truncated cubilin isoform is expressed in the intestine, C-terminal variants do not affect vitamin B12 absorption, thereby explaining the absence of malabsorption in chronic benign proteinuria associated with CUBN C-terminal variants.