Polymorphisms in the C-type lectin genes cluster in chromosome 19 and predisposition to severe acute respiratory syndrome coronavirus (SARS-CoV) infection

Li, H.; Tang, Nelson L.S.; Chan, Paul K.S.; Wang, C.-Y.; Hui, David S.; Luk, Chun Shui; Kwok, Raymond; Huang, Weihuan; Sung, Joseph J.Y.; Kong, Qing‐Peng; Zhang, Y.-P.

doi:10.1136/jmg.2008.058966

Cited by 22 publications

(22 citation statements)

References 30 publications

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“…The VNTR polymorphism in exon 4 of CLEC4M was genotyped using the same polymerase chain reaction protocol as described previously. 29 The genotype of the SNP, rs868875 studied in the CHARGE GWAS, was determined using the polymerase chain reaction-RFLP protocol described previously by Li et al 30 To validate the genotyping results, 10% of the samples were genotyped again by duplicate genotyping experiments.…”

Section: Determination Of the Vntr Genotype And Snp Rs868875mentioning

confidence: 99%

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

Rydz

Swystun

Notley

et al. 2013

Blood

105

121

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Key Points• CLEC4M plays a role in the clearance of VWF.• CLEC4M polymorphisms contribute to the genetic variability of VWF plasma levels.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 5 .0096) and an association of this allele with increased VWF:RCo (P 5 .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 5 .006). Mice expressing CLEC4M after hydrodynamic liver transfer have a 46% decrease in plasma levels of VWF (P 5 .0094). CLEC4M binds to and internalizes VWF, and polymorphisms in the CLEC4M gene contribute to variable plasma levels of VWF. (Blood. 2013;121(26):5228-5237) Introduction von Willebrand factor (VWF) is a plasma glycoprotein that mediates platelet adhesion and aggregation and acts as the carrier protein for factor VIII (FVIII). VWF synthesis by endothelial cells 1 and megakaryocytes 2 involves complex post-translational modifications including dimerization, glycosylation, sulfation, multimerization, and propeptide cleavage (reviewed by Sadler 3 ). The protein is either constitutively secreted into the plasma and subendothelium or is stored in endothelial Weibel-Palade bodies or platelet a granules from which release can be mediated by a number of chemical and biomechanical stimuli.Plasma VWF levels in healthy participants show a fourfold range (0.50-2.00 IU/mL). 4 These levels are influenced by a variety of genetic and acquired factors. ABO blood group contributes approximately 30% of the genetic influence, 5,6 whereas age, 6,7 acute-phase stimuli, [8][9][10] and several endocrine abnormalities represent acquired determinants of VWF levels. 7,11 In type 1 von Willebrand disease (VWD), which is defined as a partial deficiency of functionally normal VWF, approximately 35% of individuals do not have a putative mutation in the coding region, splice junctions, or proximal promoter of the VWF gene, suggesting that genes other than VWF may contribute to the pathophysiology of this disease. 12,13 VWF circulates in a tight, noncovalently linked complex with FVIII. The mean circulating half-lives of VWF and FVIII are 12 to 18 hours and12 hours, respectively, but details of the fate of both proteins are minimal. Evidence exists that cells in the li...

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Section: Determination Of the Vntr Genotype And Snp Rs868875mentioning

confidence: 99%

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

Rydz

Swystun

Notley

et al. 2013

Blood

105

121

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“…DC-SIGN might be a crucial part in host immunity to tuberculosis and one of the candidate genes for susceptibility to tuberculosis. In addition, it has been reported that the variants of DC-SIGN have been linked to susceptibility to several other infectious diseases, such as HIV-1 [7], Dengue [8], and severe acute respiratory syndrome (SARS) [9]. The research on DC-SIGN genetic variability and its association with tuberculosis mainly focused on two regions: promoter and neck.…”

Section: Introductionmentioning

confidence: 99%

Relationship between polymorphism of DC-SIGN (CD209) gene and the susceptibility to pulmonary tuberculosis in an eastern Chinese population

et al. 2011

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Dendritic cell-specific intracellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) is an important receptor for Mycobacterium tuberculosis on human dendritic cells. Previous studies have shown that the variation, especially the -871A/G and -336A/G in DC-SIGN promoter influenced the susceptibility to tuberculosis. We therefore investigated whether polymorphisms in the DC-SIGN gene were associated with susceptibility to tuberculosis in an eastern Chinese population. A total of 237 culture-positive pulmonary tuberculosis case patients and 244 controls were genotyped for -871A/G and -336A/G by pyrosequencing. Our results suggested that the 2 promoter variants of DC-SIGN gene were not associated with susceptibility to tuberculosis in Chinese. Further analysis showed that the allele -336G was associated with a protective effect against fever in pulmonary tuberculosis patients, but not against cavity formation. In addition, we compared the allelic frequencies of -871A/G and -336A/G in African, Caucasian, and Asian groups. The results showed that the tw forms of allelic frequencies detected Chinese individuals in our study were similar to the reported frequencies in other Asian populations but differed significantly from those in the African and Caucasian groups studied.

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“…This arrangement of very stable repeat units in the neck domain, which is conserved in all of the DC‐SIGNR proteins in the primates, may be necessary to ensure that the neck domain remains tetrameric even though the final repeat units are splayed apart by the presence of the phenylalanine residue. The studies reported here suggest that the presence of stabilizing residues at positions 6 and 15 of the repeat units allows for the formation of stable tetramers even for shorter versions of the neck domain present in some individuals, which result from common genetic polymorphisms in the human population . However, the results also define a minimal length for the neck domain to be fully stable, even in the presence of stabilizing residues within the repeat units.…”

Section: Discussionmentioning

confidence: 59%

Oligomerization domains in the glycan‐binding receptors DC‐SIGN and DC‐SIGNR: Sequence variation and stability differences

et al. 2016

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Human dendritic cell‐specific intercellular adhesion molecule‐1 grabbing nonintegrin, DC‐SIGN, and the sinusoidal endothelial cell receptor DC‐SIGNR or L‐SIGN, are closely related sugar‐binding receptors. DC‐SIGN acts both as a pathogen‐binding endocytic receptor and as a cell adhesion molecule, while DC‐SIGNR has only the pathogen‐binding function. In addition to differences in the sugar‐binding properties of the carbohydrate‐recognition domains in the two receptors, there are sequence differences in the adjacent neck domains, which are coiled‐coil tetramerization domains comprised largely of 23‐amino acid repeat units. A series of model polypeptides consisting of uniform repeat units have been characterized by gel filtration, differential scanning calorimetry and circular dichroism. The results demonstrate that two features characterize repeat units which form more stable tetramers: a leucine reside in the first position of the heptad pattern of hydrophobic residues that pack on the inside of the coiled coil and an arginine residue on the surface of the coiled coil that forms a salt bridge with a glutamic acid residue in the same polypeptide chain. In DC‐SIGNR from all primates, very stable repeat units predominate, so the carbohydrate‐recognition domains must be held relatively closely together. In contrast, stable repeat units are found only near the membrane in DC‐SIGN. The presence of residues that disrupt tetramer formation in repeat units near the carbohydrate‐recognition domains of DC‐SIGN would allow these domains to splay further apart. Thus, the neck domains of DC‐SIGN and DC‐SIGNR can contribute to the different functions of these receptors by presenting the sugar‐binding sites in different contexts.

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Polymorphisms in the C-type lectin genes cluster in chromosome 19 and predisposition to severe acute respiratory syndrome coronavirus (SARS-CoV) infection

Abstract: The results indicated that the genetic predisposition allele was not found in this lectin gene cluster and population stratification might cause the previous positive association.

Cited by 22 publications

References 30 publications

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

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

Relationship between polymorphism of DC-SIGN (CD209) gene and the susceptibility to pulmonary tuberculosis in an eastern Chinese population

Oligomerization domains in the glycan‐binding receptors DC‐SIGN and DC‐SIGNR: Sequence variation and stability differences

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