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von Willebrand factor variants in C3 glomerulopathy: A Chinese cohort study
Yun-Ying Chen1, Sha-Sha Han2, Yang Cao3
1Renal Division, Department of Medicine, Peking University First Hospital; Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China; Beijing 100034, PR China.
Insights
Rare kidney disease C3 glomerulopathy (C3G) involves complement dysregulation. This study found mutations in the von Willebrand factor (VWF) gene are surprisingly common in C3G patients, suggesting VWF
Area of Science:
- Nephrology
- Genetics
- Immunology
Background:
- C3 glomerulopathy (C3G) is a rare renal disease defined by C3 deposition in glomeruli.
- Dysregulation of the complement alternative pathway, often due to genetic defects, is implicated in C3G pathogenesis.
Purpose of the Study:
- To identify novel genes associated with C3G.
- To investigate the role of complement, coagulation, and endothelial system genes in C3G.
Main Methods:
- Targeted genomic enrichment and massively parallel sequencing were used.
- 86 genes were screened in 35 C3G patients.
- In vitro expression studies of von Willebrand factor (VWF) variants were performed.
Main Results:
- The von Willebrand factor (VWF) gene was the most frequently mutated gene identified.
- Patients with VWF variants exhibited increased proteinuria, crescent formation, and lower factor H (FH) levels.
- In vitro studies showed reduced VWF expression for a specific variant and demonstrated VWF's ability to bind FH and C3b, acting as a cofactor for factor I.
Conclusions:
- VWF variants are associated with C3G and may contribute to disease pathogenesis.
- VWF plays a role in regulating complement activation by interacting with FH and C3b.
- VWF is a potential novel therapeutic target or biomarker for C3G.
Abstract:
C3 glomerulopathy (C3G) is a rare renal disease characterized by predominant glomerular C3 staining. Complement alternative pathway dysregulation due to inherited complement defects is associated with C3G. To identify novel C3G-related genes, we screened 86 genes in the complement, coagulation and endothelial systems in 35 C3G patients by targeted genomic enrichment and massively parallel sequencing. Surprisingly, the most frequently mutated gene was VWF. Patients with VWF variants had significantly higher proteinuria levels, higher crescent formation and lower factor H (FH) levels. We further selected two VWF variants to transiently express the von Willebrand factor (vWF) protein, we found that vWF expression from the c.1519A > G variant was significantly reduced. In vitro results further indicated that vWF could regulate complement activation, as it could bind to FH and C3b, act as a cofactor for factor I-mediated cleavage of C3b. Thus, we speculated that vWF might be involved in the pathogenesis of C3G.
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