ArticleJournal of translational medicine2022
Novel pathogenic variants in CUBN uncouple proteinuria from renal function.
Article in Journal of translational medicine, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 7 citations in OpenAlex.
- Molecular Genetics Solves the Conundrum of Two Brothers Affected With Proteinuria Coming With a Very Different Flavor: A Case Report.Kidney medicine · 2025Article
- [Clinicopathological significance and prognostic value of serum 25-hydroxyvitamin DZhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics · 2025Article
- To treat or not to treat: CUBN-associated persistent proteinuria.Kidney research and clinical practice · 2024Article
- Identification of novel pathogenic variants of CUBN in patients with isolated proteinuria.Molecular genetics & genomic medicine · 2024Article
- The pathogenesis of albuminuria in cadmium nephropathy.Current research in toxicology · 2024Article
- Isolated benign persistent proteinuria with novel association ofClinical case reports · 2023Article
- Four missense genetic variants inFrontiers in endocrinology · 2023Article
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11 authors at 2 institutions in 1 country.
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Abstract
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.
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