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.

A 3-year-old boy presented with dark-colored urine for 4 months. His history was negative for infections, but he was taking oral methylcobalamin treatment for a persistent deficiency. His parents were first-degree cousins, and a female cousin had proteinuria of unknown etiology. A physical examination and laboratory examination revealed no abnormalities except for non-orthostatic nephritic proteinuria and low levels of vitamin B12. Albumin was the main protein in the urine. Kidney biopsy showed nonspecific changes. Genetic analysis identified a homozygous pathogenic AMN mutation, confirming Imerslund-Grâsbeck syndrome (IGS). Angiotensin-converting enzyme inhibitor was prescribed but discontinued due to stable protein levels. After 4 years, kidney function remained stable. Imerslund-Grâsbeck syndrome is a rare autosomal recessive disorder that affects vitamin B12 and protein, particularly albumin absorption. While typically presenting with megaloblastic anemia, AMN mutations show variable phenotypes. Proteinuria is resistant to ACE inhibitors, and currently, there is no specific treatment.

Imerslund-Gräsbeck Syndrome (IGS) is a rare autosomal recessive disorder characterized by selective cobalamin (vitamin B12) malabsorption and often accompanied by proteinuria. Mutations in CUBN or AMN genes underlie the condition, which usually manifests in childhood with megaloblastic anemia, failure to thrive, or recurrent infections. We report a 15-year-old Iranian boy with a 12-year history of recurrent anemia and intermittent proteinuria. He presented with fatigue, nausea, and anorexia. Laboratory evaluation showed pancytopenia, macrocytic anemia (Hb 7.5 g/dL → 6.9 g/dL), thrombocytopenia (91 × 10³/µL → 38 × 10³/µL), and a severely reduced serum vitamin B12 level (74.4 pg/mL). Liver enzymes were elevated (AST 346 U/L, ALT 225 U/L), while renal function was preserved. Bone marrow aspiration confirmed megaloblastic changes. Despite the lack of confirmatory genetic testing, the diagnosis of IGS was made based on clinical findings and hematologic response. Treatment with intramuscular hydroxocobalamin (1000 mcg/day) and folic acid resulted in marked improvement, with hemoglobin rising to 11.4 g/dL and normalization of blood counts within three weeks. Intermittent proteinuria persisted. This case emphasizes the importance of considering IGS in children and adolescents with unexplained macrocytic anemia and proteinuria, particularly in the Middle East where the condition is underdiagnosed. Early recognition and lifelong vitamin B12 supplementation are critical to prevent irreversible complications such as neurological deficits, developmental delay, and growth impairment.

Imerslund-Gräsbeck syndrome (IGS) is a rare genetic disorder characterized by selective vitamin B12 deficiency co-existing with asymptomatic proteinuria. It is caused by bi-allelic mutations in either the CUBN or AMN gene, which encode the two protein components of the cobalamin-intrinsic factor receptor. Patients stay healthy with lifelong parenteral administration of vitamin B12. Here, we report a case of a young male who presented with severe macrocytic anemia and asymptomatic proteinuria from the age of one year. His low serum level of vitamin B12 suggested vitamin B12 deficiency. Further, the patient was heterozygous for the AMN variant c.1006 + 34_1007-31 del mutation with duplication of exons 2-3, indicating a definite diagnosis of typical IGS. He was treated by administration of vitamin B12 injections, resulting in rapid improvement of hemoglobin levels. However, the previously detected proteinuria was found to persist at follow-up.