Isolated benign persistent proteinuria with novel association of CUBN (cubilin) variants.
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ABSTRACT:
SUBMITTER: Shi V
PROVIDER: S-EPMC10258721 | biostudies-literature | 2023 Jun
REPOSITORIES: biostudies-literature
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Isolated benign persistent proteinuria with novel association of <i>CUBN</i> (cubilin) variants.
Shi Vivian V Stein Quinn Q Clark Dinah D Punj Sumit S Kremsdorf Robin R Faizan Mohammed M
Clinical case reports 20230612 6
We present two siblings with persistent proteinuria and normal kidney function, each carrying the same compound heterozygous variants in the <i>CUBN</i> gene. The <i>CUBN</i>-related phenotype appears to be dependent upon both variant type and the domain site within the gene. Knowledge of <i>CUBN</i> status may allow for avoidance of invasive testing. ...[more]
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Project description:BackgroundAlthough proteinuria is long recognized as an independent risk factor for progressive chronic kidney diseases, not all forms of proteinuria are detrimental to kidney function, one of which is isolated proteinuria caused by cubilin (CUBN)-specific mutations. CUBN encodes an endocytic receptor, initially found to be responsible for the Imerslund-Gräsbeck syndrome (IGS; OMIM #261100) characterized by a combined phenotype of megaloblastic anemia and proteinuria.MethodsAfter analyzing their clinical and pathological characterizations, next-generation sequencing for renal disease genes or whole-exome sequencing (WES) was performed on four patients with non-progressive isolated proteinuria. CUBN biallelic pathogenic variants were identified and further analyzed by cDNA-PCR sequencing, immunohistochemistry, minigene assay, and multiple in silico prediction tools, including 3D protein modeling.ResultsHere, we present four patients with isolated proteinuria caused by CUBN C-terminal biallelic pathogenic variants, all of which showed no typical IGS symptoms, such as anemia and vitamin B12 deficiency. Their urine protein levels fluctuated between +~++ and estimated glomerular filtration rate (eGFR) were normal or slightly higher. Mild mesangial hypercellularity was found in three children's renal biopsies. A homozygous splice-site variant of CUBN (c.6821+3 (IVS44) A>G) was proven to result in the exon 44 skipping and premature translation termination by cDNA sequencing and immunohistochemistry. Compound heterozygous mutations were identified among the other three children, including another novel splice-site variant (c.10764+1 (IVS66) G>A) causing the retention of first 4 nucleotides in intron 66 by minigene assay, two unreported missense mutations (c.4907G>A (p.R1636Q); c. 9095 A>G (p.Y3032C)), and two reported missense mutations in China (c.8938G>A (p.D2980N); c. 9287T>C (p.L3096P)), locating behind the vitamin B12-binding domain, affecting CUB11, CUB16, CUB22, CUB23, and CUB27 domains, respectively.ConclusionThese results demonstrate that above CUBN mutations may cause non-progressive and isolated proteinuria, expanding the variant spectrum of CUBN and benefiting our understanding of proteinuria and renal function.
| S-EPMC10941600 | biostudies-literature
Project description:BackgroundProteinuria is an unfavorable clinical condition highly associated with a risk of renal and cardiovascular disease in chronic kidney disease (CKD). However, whether all proteinuria forms are linked to renal impairment are still unclear. Cubilin is an endocytic receptor highly expressed in renal proximal tubules mediating uptake of albumin, transferrin and α1-microglobulin.MethodsExome sequencing method initially identified candidate genes. With the application of exome sequencing combined with Sanger sequencing, we further focused on CUBN through bioinformatics analysis. The pathogenic effects of the potentially causative variants were verified utilizing complementary analysis of clinical data and systematic characterization of the variants' expression and function with clinical samples and in vitro experiments in HEK293T cell lines along with in vivo experiments in mice.ResultsIn this study, we identified four novel variants locating after the vitamin B12 (vitB12)-binding domain of Cubilin (encoded by CUBN, NM_001081.3: c.4397G > A (p.C1466Y), c.6796C > T (p.R2266X), c.6821 + 3A > G and c.5153_5154delCT (p.S1718X)) in two families. Moreover, the variants severely affected the expression and function of Cubilin in renal proximal tubules and caused albuminuria, increasing levels in urine transferrin and α1-microglobulin, but without progressive glomerular filtration barrier (GFB) impairment, vitB12 deficiencies or abnormal blood levels of HDL and albumin. Further mechanistic insights showed that the variants after the vitB12-binding domain of CUBN merely disrupted the association with Amnionless (AMN) that exhibited aberrant localization in cell cytoplasm rather than membrane.ConclusionsHere, our findings suggested that different mutation types after the vitB12-binding domain of CUBN uncouple proteinuria from glomerular filtration barrier, that may be an unexpectedly common benign condition in humans and may not require any proteinuria-lowering treatment or renal biopsy.
| S-EPMC9583559 | biostudies-literature
Project description:Cubilin, (CUBN; also known as intrinsic factor-cobalamin receptor [Homo sapiens Entrez Pubmed ref NM_001081.3; NG_008967.1; GI: 119606627]), located in the epithelium of intestine and kidney acts as a receptor for intrinsic factor - vitamin B12 complexes. Mutations in CUBN may play a role in autosomal recessive megaloblastic anemia. The current study investigated the possible role of CUBN in evolution using phylogenetic testing. A total of 588 BLAST hits were found for the cubilin query sequence and these hits showed putative conserved domain, CUB superfamily (as on 27(th) Nov 2012). A first-pass phylogenetic tree was constructed to identify the taxa which most often contained the CUBN sequences. Following this, we narrowed down the search by manually deleting sequences which were not CUBN. A repeat phylogenetic analysis of 25 taxa was performed using PhyML, RAxML and TreeDyn softwares to confirm that CUBN is a conserved protein emphasizing its importance as an extracellular domain and being present in proteins mostly known to be involved in development in many chordate taxa but not found in prokaryotes, plants and yeast.. No horizontal gene transfers have been found between different taxa.
| S-EPMC3563413 | biostudies-literature
Project description:BackgroundProteinuria is a common clinical presentation, the diagnostic workup for which involves many non-invasive and invasive investigations. We report on two siblings that highlight the clinically relevant functional role of cubulin for albumin resorption in the proximal tubule and supports the use of genomic sequencing early in the diagnostic work up of patients who present with proteinuria.Case presentationAn 8-year-old boy was referred with an incidental finding of proteinuria. All preliminary investigations were unremarkable. Further assessment revealed consanguineous family history and a brother with isolated proteinuria. Renal biopsy demonstrated normal light microscopy and global glomerular basement membrane thinning on electron microscopy. Chromosomal microarray revealed long continuous stretches of homozygosity (LCSH) representing ~ 4.5% of the genome. Shared regions of LCSH between the brothers were identified and their further research genomic analysis implicated a homozygous stop-gain variant in CUBN (10p12.31).ConclusionsCUBN mutations have been implicated as a hereditary cause of megaloblastic anaemia and variable proteinuria. This is the second reported family with isolated proteinuria due to biallelic CUBN variants in the absence of megaloblastic anaemia, demonstrating the ability of genomic testing to identify genetic causes of nephropathy within expanding associated phenotypic spectra. Genomic sequencing, undertaken earlier in the diagnostic trajectory, may reduce the need for invasive investigations and the time to definitive diagnosis for patients and families.
| S-EPMC6704575 | biostudies-literature
Project description:Background and objectivesGenetic variation in the cubilin (CUBN) gene is associated with albuminuria and CKD. Common and rare coding variants in CUBN and the gene encoding its transport partner megalin (LRP2) were assessed for association with ESRD in blacks.Design, setting, participants, & measurementsSixty-six CUBN and LRP2 single-nucleotide polymorphisms (SNPs) were selected and analyzed in this multistage study. Exome sequencing data from 529 blacks with type 2 diabetes (T2D) -associated ESRD and 535 controls lacking T2D or nephropathy (the Type 2 Diabetes Genes [T2D-GENES] Consortium) were first evaluated, focusing on coding variants in CUBN and LRP2; 15 potentially associated SNPs identified from the T2D-GENES Consortium as well as 51 other selected SNPs were then assessed in an independent T2D-ESRD sample set of blacks (the Affymetrix Axiom Biobank Genotyping Array [AXIOM]; 2041 patients with T2D-ESRD, 627 patients with T2D without nephropathy, and 1140 nondiabetic, non-nephropathy controls). A meta-analysis combining the T2D-GENES Consortium and the AXIOM data was performed for 18 overlapping SNPs. Additionally, all 66 SNPs were genotyped in the Wake Forest School of Medicine samples of blacks with nondiabetic ESRD (885 patients with nondiabetic ESRD and 721 controls). Association testing with ESRD was performed in models including age, sex, African ancestry proportion, and apolipoprotein L1 gene renal-risk variants.ResultsCUBN SNP rs1801239 (I2984V), previously associated with albuminuria, was significantly associated with T2D-ESRD in blacks (the T2D-GENES Consortium and the AXIOM meta-analysis, P=0.03; odds ratio, 1.31; 95% confidence interval, 1.03 to 1.67; minor allele frequency =0.028). A novel LRP2 missense variant, rs17848169 (N2632D), was also significantly protective from T2D-ESRD (the T2D-GENES Consortium and the AXIOM, P<0.002; odds ratio, 0.47; 95% confidence interval, 0.29 to 0.75; meta-analysis minor allele frequency =0.007). Neither SNP was associated with T2D when contrasting patients with T2D with controls lacking diabetes. CUBN and LRP2 SNPs were not associated with nondiabetic etiologies of ESRD.ConclusionsEvidence for genetic association exists between a cubilin and a rare megalin variant with diabetes-associated ESRD in populations with recent African ancestry.
| S-EPMC4891762 | biostudies-literature
Project description:BACKGROUNDProteinuria is considered an unfavorable clinical condition that accelerates renal and cardiovascular disease. However, it is not clear whether all forms of proteinuria are damaging. Mutations in CUBN cause Imerslund-Gräsbeck syndrome (IGS), which is characterized by intestinal malabsorption of vitamin B12 and in some cases proteinuria. CUBN encodes for cubilin, an intestinal and proximal tubular uptake receptor containing 27 CUB domains for ligand binding.METHODSWe used next-generation sequencing for renal disease genes to genotype cohorts of patients with suspected hereditary renal disease and chronic proteinuria. CUBN variants were analyzed using bioinformatics, structural modeling, and epidemiological methods.RESULTSWe identified 39 patients, in whom biallelic pathogenic variants in the CUBN gene were associated with chronic isolated proteinuria and early childhood onset. Since the proteinuria in these patients had a high proportion of albuminuria, glomerular diseases such as steroid-resistant nephrotic syndrome or Alport syndrome were often the primary clinical diagnosis, motivating renal biopsies and the use of proteinuria-lowering treatments. However, renal function was normal in all cases. By contrast, we did not found any biallelic CUBN variants in proteinuric patients with reduced renal function or focal segmental glomerulosclerosis. Unlike the more N-terminal IGS mutations, 37 of the 41 proteinuria-associated CUBN variants led to modifications or truncations after the vitamin B12-binding domain. Finally, we show that 4 C-terminal CUBN variants are associated with albuminuria and slightly increased GFR in meta-analyses of large population-based cohorts.CONCLUSIONCollectively, our data suggest an important role for the C-terminal half of cubilin in renal albumin reabsorption. Albuminuria due to reduced cubilin function could be an unexpectedly common benign condition in humans that may not require any proteinuria-lowering treatment or renal biopsy.FUNDINGATIP-Avenir program, Fondation Bettencourt-Schueller (Liliane Bettencourt Chair of Developmental Biology), Agence Nationale de la Recherche (ANR) Investissements d'avenir program (ANR-10-IAHU-01) and NEPHROFLY (ANR-14-ACHN-0013, to MS), Steno Collaborative Grant 2018 (NNF18OC0052457, to TSA and MS), Heisenberg Professorship of the German Research Foundation (KO 3598/5-1, to AK), Deutsche Forschungsgemeinschaft (DFG) Collaborative Research Centre (SFB) KIDGEM 1140 (project 246781735, to CB), and Federal Ministry of Education and Research (BMB) (01GM1515C, to CB).
| S-EPMC6934218 | biostudies-literature
Project description:Mutations in the cubilin (CUBN) gene commonly cause Imerslund-Gräsbeck syndrome, while isolated proteinuria as a result of CUBN variations is rarely reported. The clinical manifestation is mainly chronic isolated proteinuria in the non-nephrotic range. However, findings to date suggest that isolated proteinuria associated with abnormalities in the CUBN gene is benign and does not affect long-term prognosis of kidney function. We identified 2 patients with isolated proteinuria triggered by compound heterozygous CUBN mutations. Renal functions of both patients remained normal over a 10-year follow-up period, supporting the benign nature of proteinuria caused by CUBN gene variations. Two novel mutation sites were detected, expanding the genotypic spectrum of CUBN variations. In addition, etiology, pathogenesis, clinical manifestations, auxiliary examination, and treatment of the condition were reviewed, with the aim of providing further guidance for clinical management.
| S-EPMC10293958 | biostudies-literature
Project description:In two siblings of consanguineous parents with intermittent nephrotic-range proteinuria, we identified a homozygous deleterious frameshift mutation in the gene CUBN, which encodes cubulin, using exome capture and massively parallel re-sequencing. The mutation segregated with affected members of this family and was absent from 92 healthy individuals, thereby identifying a recessive mutation in CUBN as the single-gene cause of proteinuria in this sibship. Cubulin mutations cause a hereditary form of megaloblastic anemia secondary to vitamin B(12) deficiency, and proteinuria occurs in 50% of cases since cubilin is coreceptor for both the intestinal vitamin B(12)-intrinsic factor complex and the tubular reabsorption of protein in the proximal tubule. In summary, we report successful use of exome capture and massively parallel re-sequencing to identify a rare, single-gene cause of nephropathy.
| S-EPMC3187182 | biostudies-literature
Project description:Imerslund-Gräsbeck syndrome (IGS) or selective cobalamin malabsorption has been described in humans and dogs. IGS occurs in Border Collies and is inherited as a monogenic autosomal recessive trait in this breed. Using 7 IGS cases and 7 non-affected controls we mapped the causative mutation by genome-wide association and homozygosity mapping to a 3.53 Mb interval on chromosome 2. We re-sequenced the genome of one affected dog at ∼10× coverage and detected 17 non-synonymous variants in the critical interval. Two of these non-synonymous variants were in the cubilin gene (CUBN), which is known to play an essential role in cobalamin uptake from the ileum. We tested these two CUBN variants for association with IGS in larger cohorts of dogs and found that only one of them was perfectly associated with the phenotype. This variant, a single base pair deletion (c.8392delC), is predicted to cause a frameshift and premature stop codon in the CUBN gene. The resulting mutant open reading frame is 821 codons shorter than the wildtype open reading frame (p.Q2798Rfs*3). Interestingly, we observed an additional nonsense mutation in the MRC1 gene encoding the mannose receptor, C type 1, which was in perfect linkage disequilibrium with the CUBN frameshift mutation. Based on our genetic data and the known role of CUBN for cobalamin uptake we conclude that the identified CUBN frameshift mutation is most likely causative for IGS in Border Collies.
| S-EPMC3628801 | biostudies-literature
Project description:Previous studies have demonstrated the association between the occurrence of leprosy and several host genetic variants that can vary across different ethnic groups and populations. Since leprosy susceptibility genes have not been investigated in detail in the Bangladeshi population that still includes highly endemic areas, we here studied known associations between leprosy and 13 genetic markers located in 11 genes in a leprosy endemic area in Bangladesh for which an association with leprosy was previously found in an isolated former leprosy colony in the Brazilian Amazon. For this study, a family-based analysis using 60 parent-affected child trios was performed, followed by a case-control study of 210 leprosy patients and 189 healthy controls from the same area (endemic controls). Genotypes for 11 markers were determined by TaqMan SNP genotyping. In the family-based study, a significant association was found between leprosy and three single nucleotide polymorphisms, rs1801224, rs13001714, and rs1801582, located in the CUBN, IL1RL1, and PRKN genes, respectively. These findings were not replicated in the case-control sample. Variants in the CUBN, IL1RL1, and PRKN genes were associated with leprosy in Bangladesh, validating the initial Brazilian finding in a population sample of distinct ethnic background.
| S-EPMC11880505 | biostudies-literature