title: The C-type lectin receptor CLEC4M binds, internalizes, and clears von Willebrand factor and contributes to the variation in plasma von Willebrand factor levels.
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.
authors.affiliation: Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada.
authors.forename: Natalia
authors.initials: N
authors.lastname: Rydz
authors.forename: Laura L
authors.initials: LL
authors.lastname: Swystun
authors.forename: Colleen
authors.initials: C
authors.lastname: Notley
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Paterson
authors.forename: J Jacob
authors.initials: JJ
authors.lastname: Riches
authors.forename: Kate
authors.initials: K
authors.lastname: Sponagle
authors.forename: Boonchai
authors.initials: B
authors.lastname: Boonyawat
authors.forename: Robert R
authors.initials: RR
authors.lastname: Montgomery
authors.forename: Paula D
authors.initials: PD
authors.lastname: James
authors.forename: David
authors.initials: D
authors.lastname: Lillicrap
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005190:Family; D005260:Female; D005434:Flow Cytometry; D055106:Genome-Wide Association Study; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D007124:Immunoenzyme Techniques; D007223:Infant; D037181:Lectins, C-Type / Q000235:genetics* / Q000378:metabolism*; D015810:Linkage Disequilibrium; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D018598:Minisatellite Repeats / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D055815:Young Adult; D014842:von Willebrand Diseases / Q000097:blood* / Q000235:genetics / Q000473:pathology; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D037181:Lectins, C-Type; D014841:von Willebrand Factor; D004247:DNA