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Novel pathogenic variants in CUBN uncouple proteinuria from renal function
Chun Gan1, Xindi Zhou1, Dan Chen1
1Pediatric Research Institute, Department of Nephrology, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
Insights
Novel variants in the CUBN gene cause proteinuria without kidney damage. This suggests some forms of proteinuria may be benign, not requiring treatment or biopsy.
Area of Science:
- Genetics and Molecular Biology
- Nephrology
- Biochemistry
Background:
- Proteinuria is a risk factor for kidney and cardiovascular disease in chronic kidney disease (CKD).
- The role of all proteinuria types in renal impairment is not fully understood.
- Cubilin is a key endocytic receptor in renal proximal tubules for albumin, transferrin, and α1-microglobulin uptake.
Purpose of the Study:
- To investigate novel genetic variants affecting the Cubilin (CUBN) protein.
- To determine the functional consequences of these variants on kidney function and proteinuria.
- To clarify the relationship between specific proteinuria types and glomerular filtration barrier integrity.
Main Methods:
- Exome and Sanger sequencing to identify candidate genes and variants.
- Bioinformatics analysis to focus on the CUBN gene.
- In vitro (HEK293T cells) and in vivo (mice) experiments to assess variant expression and function.
- Clinical data analysis of affected families.
Main Results:
- Four novel CUBN variants were identified in two families, located after the vitamin B12-binding domain.
- These variants impaired Cubilin expression and function, leading to increased urinary albumin, transferrin, and α1-microglobulin.
- Importantly, no progressive glomerular filtration barrier impairment, vitamin B12 deficiency, or abnormal blood lipid/albumin levels were observed.
Conclusions:
- Mutations in CUBN after the vitamin B12-binding domain can uncouple proteinuria from glomerular filtration barrier damage.
- This suggests a potentially common, benign form of proteinuria in humans.
- Such cases may not necessitate proteinuria-lowering treatments or renal biopsy.
Background:
Proteinuria 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.
Methods:
Exome 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.
Results:
In 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.
Conclusions:
Here, 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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