Abstract: TH-PO503
Chronic Benign Tubular Proteinuria from Compound Heterozygous Mutations in CUBN: A Case Report
Session Information
- Genetic Kidney Diseases: Genotypes and Phenotypes in Cases
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Pietrobon, Adam, The University of British Columbia Faculty of Medicine, Vancouver, British Columbia, Canada
- Elliott, Mark, The University of British Columbia Faculty of Medicine, Vancouver, British Columbia, Canada
Introduction
Proteinuria is a commonly used parameter for predicting decline in renal filtration function. Cubilin, encoded by CUBN, is a critical protein involved in low molecular weight protein reabsorption in the proximal tubule. Mutations in CUBN lead to Imerslund-Gräsbeck syndrome (IGS), a disorder characterized by vitamin B12 deficiency (and consequences related to that) with or without proteinuria. Recent evidence suggests that C-terminal mutations in CUBN may lead to proteinuria without other features of IGS.
Case Description
We report a case of a 47 year-old male with chronic, albumin-predominant, subnephrotic range proteinuria since his teenage years, but preserved eGFR. Neither ACE inhibition nor AT-II receptor blockade reduced his degree of proteinuria. Genetic testing identified three distinct pathogenic mutations in CUBN that were confirmed by parental cascade testing to be compound heterozygosity. All mutations were downstream of the vitamin B12-intrinsic factor binding domain of cubilin, two of which conferred stop-gain sequences. The patient had normal vitamin B12 levels and did not exhibit megaloblastic anemia, growth retardation, or any other features of IGS. Renal biopsy was not pursued for this patient as diagnostic clarification was achieved by non-invasive genetic testing alone.
Discussion
This case report presents the first long-term follow-up of a patient with CUBN mutations, demonstrating eGFR stability despite chronic proteinuria. We highlight several important lessons. First, not all proteinuria is made equal, and forms of tubular proteinuria can exist without compromising renal filtration function. Second, identifying genetic forms of tubular proteinuria is key to avoiding ineffective interventions (e.g. ACE inhibition, AT-II receptor blockade) and unnecessary invasive procedures (e.g. renal biopsy). Third, the location of CUBN mutations dictate phenotypic consequences, with C-terminal mutations leading to proteinuria without vitamin B12 deficiency.