The C-type lectin receptor CLEC4M binds, internalizes, and clears von Willebrand factor and contributes to the variation in plasma von Willebrand factor levels

Blood. 2013 Jun 27;121(26):5228-37. doi: 10.1182/blood-2012-10-457507. Epub 2013 Mar 25.

Abstract

Genetic variation in or near the C-type lectin domain family 4 member M (CLEC4M) has been associated with plasma levels of von Willebrand factor (VWF) in healthy individuals. CLEC4M is a lectin receptor with a polymorphic extracellular neck region possessing a variable number of tandem repeats (VNTR). A total of 491 participants (318 patients with type 1 von Willebrand disease [VWD] and 173 unaffected family members) were genotyped for the CLEC4M VNTR polymorphism. Family-based association analysis on kindreds with type 1 VWD demonstrated an excess transmission of VNTR 6 to unaffected individuals (P = .0096) and an association of this allele with increased VWF:RCo (P = .029). CLEC4M-Fc bound to VWF. Immunofluorescence and enzyme-linked immunosorbent assay demonstrated that HEK 293 cells transfected with CLEC4M bound and internalized VWF. Cells expressing 4 or 9 copies of the CLEC4M neck region VNTR showed reduced interaction with VWF relative to CLEC4M with 7 VNTR (CLEC4M 4%-60% reduction, P < .001; CLEC4M 9%-45% reduction, P = .006). Mice expressing CLEC4M after hydrodynamic liver transfer have a 46% decrease in plasma levels of VWF (P = .0094). CLEC4M binds to and internalizes VWF, and polymorphisms in the CLEC4M gene contribute to variable plasma levels of VWF.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Case-Control Studies
  • Child
  • Child, Preschool
  • DNA / genetics
  • Enzyme-Linked Immunosorbent Assay
  • Family
  • Female
  • Flow Cytometry
  • Genome-Wide Association Study
  • Genotype
  • HEK293 Cells
  • Humans
  • Immunoenzyme Techniques
  • Infant
  • Lectins, C-Type / genetics*
  • Lectins, C-Type / metabolism*
  • Linkage Disequilibrium
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice
  • Middle Aged
  • Minisatellite Repeats / genetics*
  • Polymerase Chain Reaction
  • Polymorphism, Genetic / genetics*
  • Young Adult
  • von Willebrand Diseases / blood*
  • von Willebrand Diseases / genetics
  • von Willebrand Diseases / pathology
  • von Willebrand Factor / metabolism*

Substances

  • Lectins, C-Type
  • von Willebrand Factor
  • DNA