CUBN gene mutations may cause focal segmental glomerulosclerosis (FSGS) in children

Abstract

Background Imerslund-Gräsbeck Syndrome (IGS) is mainly caused by CUBN gene biallelic mutations. Proteinuria accompanies IGS specific symptoms in about half of the patients, isolated proteinuria is rarely reported. Here we present 3 patients with isolated proteinuria and focal segmental glomerulosclerosis (FSGS) caused by CUBN gene biallelic pathogenic variants. Method Whole exome sequencing was performed on three children with isolated proteinuria. CUBN gene biallelic pathogenic variants were found and then verified by sanger sequencing. Their clinical, pathological and molecular genetic characteristics were analyzed and correlated accordingly. Results All three children presented with isolated proteinuria, no megaloblastic anemia. Their urine levels of β2 microglobulin were normal or slightly higher. Renal biopsies showed focal segmental glomerulosclerosis with mild glomerular mesangial hypercellularity, partial effacement of foot processes and podocyte microvillation. Two of them were found to carry compound heterozygous mutations and one homozygous mutation of CUBN gene. Totally four CUBN gene biallelic pathogenic variants were identified, including c.9287 T > C (p.L3096P), c.122 + 1G > A, c.7906C > T (p.R2636*), c.10233G > A (p.W3411*). Except for intron splice-site mutation, all other variants are located in highly conserved sites of CUB domain for binding to albumin. Conclusion The results demonstrate that CUBN gene mutations may cause isolated proteinuria pathologically presented as FSGS. Our cases extend the spectrum of renal manifestation and genotype of CUBN gene mutations.

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

“…Histopathology examination raised suspicion of Alport syndrome. Podocyte hypertrophy and effacement of their foot processes (usually associated with proteinuria) are common to both entities and they were already described in the literature in pediatric patients with CUBN gene mutations [6]. Other studies described minimal, unspecific or not present renal lesions on biopsies [7].…”

“…Cubilin (CUBN) is a large glycosylated extracellular protein, first identified as the vitamin B12/intrinsic factor complex receptor of the ileal mucosa. In the kidney, it was initially detected in proximal tubular cells [3][4][5], and later in podocytes [4,6]. It acts as ligand-binding site for albumin, intrinsic factor-B12 complex, vitamin carrier proteins, lipoproteins and other proteins, promoting the endocytosis of these ligands.…”

“…The majority of albumin in primary urine (approximately 3g per day) is reabsorbed through cubilin-mediated endocytosis, resulting in very small amount of albumin in the final urine [3]. Isolated persistent proteinuria caused by cubilin gene mutations is rare, only a few cases have been reported in the literature and even fewer patients underwent renal biopsy and electron microscopy that could help to elucidate the pathogenesis of the disease [6].…”

Identification of biomarkers and pathways for focal segmental glomerulosclerosis using next generation sequencing data and bioinformatics analysis

“…A recent investigation identified PDK4 [374], ALB (albumin) [375], CYP27B1 [376], PCK1 [377], TET2 [378], EGF (epidermal growth factor) [379], LPL (lipoprotein lipase) [380], PLG (plasminogen) [381], NR4A2 [382], SLC1A1 [383], OGT (O-linked N-acetylglucosamine (GlcNAc) transferase) [384], ERBB4 [385], L3MBTL3 [386], NAPEPLD (N-acyl phosphatidylethanolamine phospholipase D) [387], HTRA1 [388], CBLB (Cbl proto-oncogene B) [389], PDGFRA (platelet derived growth factor receptor alpha) [390], KL (klotho) [391], LRP2 [392], BTLA (B and T lymphocyte associated) [393], RGS1 [394], S100A12 [395], ND2 [396], CCL22 [397], ICOS (inducible T cell costimulator) [398], CNR2 [399], DBH (dopamine beta-hydroxylase) [400], CD5 [401], LTA (lymphotoxin alpha) [402], IFNG (interferon gamma) [403], MPO (myeloperoxidase) [404], CD70 [405], IRF4 [406], VAV1 [407], IKZF3 [408], BTK (Bruton tyrosine kinase) [409], LCN2 [410], TREM2 [411], CD27 [412], F12 [413], CCR5 [414], CX3CR1 [415], IL21R [416], CYBB (cytochrome b-245 beta chain) [417], IL11 [418], TRPM2 [419], EOMES (eomesodermin) [420], TNF (tumor necrosis factor) [421], CD2 [422], SEMA7A [423], TLR7 [424], CCL3 [425], NOD2 [426], CCR2 [427], CCL5 [428], TH (tyrosine hydroxylase) [429], SIGLEC1 [430], HBD (hemoglobin subunit delta) [431], NOS3 [432], SIGLEC7 [433], IL2RB [434], RETN (resistin) [435] and S100B [436] as major genes contributing to multiple sclerosis. Musante et al [437], Han et al [438], Zhang et al [439], Sato et al [440], Yang et al [441...…”

Four missense genetic variants in CUBN are associated with higher levels of eGFR in non-diabetes but not in diabetes mellitus or its subtypes: A genetic association study in Europeans

“…In healthy individuals, the glomerular filter in the kidneys retains most of the albumin, although a small amount can usually pass through to the tubular system (1). Reabsorption of albumin is facilitated by the kidney's proximal tubular cells (PTCs), ensuring that almost no albumin is excreted in urine under normal conditions (2,3). Elevated excretion of albumin in the urineinitially coined as "microalbuminuria" -is one of the earliest signs of chronic kidney disease (CKD) and may be the kidney-related manifestation of general endothelial damage, where scarring of the glomerulus causes chronic leakiness through the filter of albumin and other proteins (4).…”