von Willebrand factor variants in C3 glomerulopathy: A Chinese cohort study

Clin Immunol. 2021 Aug:229:108794. doi: 10.1016/j.clim.2021.108794. Epub 2021 Jul 8.

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.

Keywords: Alternative pathway; C3 glomerulonephritis; C3 glomerulopathy; Dense deposit disease; von Willebrand factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Case-Control Studies
  • China
  • Cohort Studies
  • Complement C3 / metabolism*
  • Complement C3b / metabolism
  • Complement Factor H / metabolism
  • Complement Pathway, Alternative
  • Female
  • Genetic Variation
  • Glomerulonephritis / genetics*
  • Glomerulonephritis / immunology
  • Glomerulonephritis / pathology
  • Glomerulonephritis, Membranoproliferative / genetics*
  • Glomerulonephritis, Membranoproliferative / immunology
  • Glomerulonephritis, Membranoproliferative / pathology
  • High-Throughput Nucleotide Sequencing
  • Humans
  • In Vitro Techniques
  • Kidney Glomerulus / immunology
  • Kidney Glomerulus / pathology
  • Male
  • Middle Aged
  • Models, Immunological
  • Molecular Dynamics Simulation
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sequence Analysis, DNA
  • Young Adult
  • von Willebrand Factor / chemistry
  • von Willebrand Factor / genetics*
  • von Willebrand Factor / metabolism

Substances

  • Complement C3
  • Recombinant Proteins
  • von Willebrand Factor
  • Complement C3b
  • Complement Factor H