Clinical and genetic characterization of a cohort of proteinuric patients with biallelic CUBN variants

Abstract

Background Proteinuria is a well-known risk factor for progressive kidney impairment. Recently, C-terminal cubilin (CUBN) variants have been associated with isolated proteinuria without progression of kidney disease. Methods Genetic testing of 347 families with proteinuria of suspected monogenic cause was performed by next-generation sequencing of a custom-designed kidney disease gene panel. Families with CUBN biallelic proteinuria-causing variants were studied at the clinical, genetic, laboratory, and pathologic levels. Results Twelve families (15 patients) bearing homozygous or compound heterozygous proteinuria-causing variants in the C-terminal CUBN gene were identified, representing 3.5% of the total cohort. We identified 14 different sequence variants, five of which were novel. The median age at diagnosis of proteinuria was 4 years (range 9 months to 44 years), and in most cases proteinuria was detected incidentally. Thirteen patients had moderate-severe proteinuria at diagnosis without nephrotic syndrome. These patients showed lack of response to angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) treatment, normal kidney biopsy, and preservation of normal kidney function over time. The two remaining patients presented a more severe phenotype, likely caused by associated comorbidities. Conclusions Identification of C-terminal pathogenic CUBN variants is diagnostic of an entity characterized by glomerular proteinuria, normal kidney histology, and lack of response to ACEi/ARB treatment. This study adds evidence and increases awareness about albuminuria caused by C-terminal variants in the CUBN gene, which is a benign condition usually diagnosed in childhood with preserved renal function until adulthood.

Podocytopathy and Glomerular Basement Membrane Anomalies in Two Patients With Cubilin Gene Mutations

“…Quental et al [12] described two siblings with CUBN gene mutations, diagnosed in adulthood, one of them with end-stage kidney disease as the inaugural manifestation. Domingo-Gallego et al [13] described 15 patients with homozygous or compound heterozygous variants in CUBN genes, 13 patients with normal renal biopsy and preservation of normal kidney function and the two remaining patients with a more severe phenotype, that was associated by the authors to comorbidities.…”

Imputation-powered whole-exome analysis identifies genes associated with kidney function and disease in the UK Biobank

“…The two genes identified through aggregate variant testing as associated with UACR, CUBN (p = 1.3 × 10 −63 ) and COL4A4 (p = 1.1 × 10 −30 ), have well-known roles in monogenic diseases that feature proteinuria 22,23 (Table 1; Supplementary Data 2). For serum urate, aggregate variant testing identified significant associations with 21 genes, six of which were not identified through ExWAS for this trait (SLC7A9, CLDN10, XDH, INSRR, RORC, and PAAF1; Table 3).…”

Isolated benign persistent proteinuria with novel association of CUBN (cubilin) variants

“…The CUBN gene, which encodes the cubilin protein, was first identified as a monogenic cause of tubular proteinuria in 2011 by Ovunc et al 6 Cubilin is a multiligand receptor that acts in concert with two transmembrane proteins, megalin and amnionless (AMN), to anchor to cell membranes. This interaction facilitates intracellular transport of cubilin–ligand complexes 2,7–9 . These proteins have limited expression in the small intestines and proximal tubules of the kidney.…”

“…10 CUBN variants noted in cases of IGS affect the N-terminal half of the encoded protein, which contains a domain responsible for vitamin B12 binding (Figure 1). 2,[10][11][12] In cases of renally isolated disease, CUBN variants affect amino acid sequence downstream of the B12 bindingdomain, suggesting that more C-terminal domains are crucial for urinary protein reabsorption, predominantly albumin (Figure 1). 2,5,[9][10][11][12] Existing literature is limited regarding the clinical manifestations and outcomes of isolated proteinuria associated with CUBN variants.…”

“…2,[10][11][12] In cases of renally isolated disease, CUBN variants affect amino acid sequence downstream of the B12 bindingdomain, suggesting that more C-terminal domains are crucial for urinary protein reabsorption, predominantly albumin (Figure 1). 2,5,[9][10][11][12] Existing literature is limited regarding the clinical manifestations and outcomes of isolated proteinuria associated with CUBN variants. The first known cases were two children born to consanguineous parents with homozygous deleterious frameshift variants in CUBN.…”