Alternative titles; symbols
HGNC Approved Gene Symbol: CLEC4M
Cytogenetic location: 19p13.2 Genomic coordinates (GRCh38) : 19:7,763,243-7,769,605 (from NCBI)
CD209 (604672), also called DCSIGN, mediates interactions between dendritic cells (DCs) and resting T cells (Bashirova et al., 2001). It also has a high affinity, exceeding that of CD4 (186940), for HIV-1 gp120. CD209-associated HIV-1 maintains its infectiousness over a prolonged period of time before transfer to T cells.
By PCR analysis of a placenta cDNA library using sequences for CD209 and a partial cDNA identified by Yokoyama-Kobayashi et al. (1999), Soilleux et al. (2000) obtained a full-length cDNA encoding CD209L, which they termed DCSIGNR. Sequence analysis predicted that CD209L is a type II integral membrane protein that is 77% identical to CD209. The CD209L protein has an N-terminal cytoplasmic tail with a dileucine motif, which is an internalization sequence; a 22-residue transmembrane domain; an N-linked glycosylation site; a neck containing 7 repeats of a 23-residue sequence; and carbohydrate recognition domains (CRDs), which are required for calcium-dependent mannose binding. The CRDs are encoded by 3 separate exons, an exonic structure also found in CD209 and CD23 (151445). RT-PCR analysis detected expression of CD209L in placenta and, at much lower levels, in endometrium and a DC line.
Bashirova et al. (2001) also obtained a cDNA encoding CD209L, which they termed LSIGN. Genomic sequence and RT-PCR analyses determined that the major transcript of CD209L is composed of 7 exons. The authors noted that there may be diversity in the number of neck domain repeats in CD209L variants. Northern blot analysis detected a major 2.6-kb transcript in liver and a 1.9-kb transcript in liver, lymph node, and, weakly, in thymus; no expression was detected in DCs. RT-PCR analysis confirmed the expression pattern reported by Soilleux et al. (2000). Immunohistochemical analysis demonstrated expression of CD209L in liver sinusoidal endothelial cells but not in DCs. Flow cytometric analysis showed that CD209L, like CD209, efficiently binds both ICAM3 (146631) and HIV-1 gp120. This binding could be inhibited by mannan and by a specific antibody. Infectivity assays established that CD209L enhances HIV-1 infection of T cells in trans in a manner similar to that of CD209. Bashirova et al. (2001) concluded that non-DC-lineage cells within liver and possibly in lymph node may be able to capture and transmit HIV-1 to lymphocytes.
By genomic sequence analysis, Soilleux et al. (2000) determined that the CD209L gene contains 8 exons.
Soilleux et al. (2000) mapped the CD209L gene to 19p13.3, in a cluster with the CD209 (604672) and CD23 genes, by radiation hybrid analysis. The lectin-coding genes CD209 and CD209L, which resulted from a duplication of an ancestral gene, are located within a segment of approximately 26 kb (Barreiro et al., 2005).
Angiotensin-converting enzyme-2 (ACE2; 300335) is a receptor for SARS-CoV, the novel coronavirus that causes severe acute respiratory syndrome (Li et al., 2003). Jeffers et al. (2004) identified a different human cellular glycoprotein, CD209L, that can serve as an alternative receptor for SARS-CoV. Immunohistochemistry showed that CD209L is expressed in human lung in type II alveolar cells and endothelial cells, both potential targets for SARS-CoV. Several other enveloped viruses, including Ebola and Sindbis, also use CD209L as a portal of entry, and HIV and hepatitis C virus can bind to CD209L on cell membranes but do not use it to mediate virus entry. The data of Jeffers et al. (2004) suggested that the large S glycoprotein of SARS-CoV may use both ACE2 and CD209L in virus infection and pathogenesis.
Feinberg et al. (2001) generated crystal structures of DCSIGN and DCSIGNR and showed that the CRDs of both are specific for high-mannose N-linked oligosaccharides, such as those present on the envelope of HIV-1. One monomer of the DCSIGN pair of CRDs interacts with the terminal N-acetylglucosamine of GlcNAc1, while the partner monomer of DCSIGNR is bound to Ca(+). Feinberg et al. (2001) proposed that the mechanistic basis of DCSIGN- and DCSIGNR-oligosaccharide interaction provides a starting point to the design of both therapeutic and prophylactic attacks on HIV-1 infection.
Gardner et al. (2003) provided an explanation for the hepatotropism of the hepatitis C virus (HCV), which infects nearly 3% of the world's population and is a major cause of liver disease (Lauer and Walker, 2001). They demonstrated that LSIGN and the homologous molecule DCSIGN--which is dendritic cell-specific, binds HIV, and promotes infection--specifically bind naturally occurring HCV present in the sera of infected individuals. Further studies demonstrated that binding is mediated by the HCV envelope glycoprotein E2 and is blocked by specific inhibitors. Thus, LSIGN represents a liver-specific receptor for HCV, and both LSIGN and DCSIGN may play important roles in HCV infection and immunity.
CLEC4M has considerable polymorphism in the tandem repeat domain of exon 4 in its extracellular region; 3 to 9 repeats of a 69-basepair segment, with 7 repeats being predominant in the general population. Chan et al. (2006) hypothesized that CLEC4M homo- or heterozygosity might affect individual susceptibility to SARS infection. They therefore performed a genetic risk association study and a series of in vitro experiments to examine the biologic role of CLEC4M in SARS infection. They found that individuals homozygous for CLEC4M tandem repeats are less susceptible to SARS infection. CLEC4M was expressed in both non-SARS and SARS-CoV-infected lung. Compared with cells heterozygous for CLEC4M, cells homozygous for CLEC4M showed higher binding capacity for SARS-CoV, higher proteasome-dependent viral degradation, and a lower capacity for trans infection. Thus, homozygosity for CLEC4M plays a protective role during SARS infection.
By comparing genotype frequencies in neonatal cord blood samples, university students, and elderly Hong Kong subjects as controls with SARS patients and controls from Beijing in northern China, Tang et al. (2007) found no support for an association between CLEC4M homozygosity and protection against SARS. By genotyping 3 additional case-control collections from Beijing and from Tianjin, including SARS-infected and seronegative individuals and health care workers, Zhi et al. (2007) also found that the protective effect of CLEC4M homozygosity could not be replicated. In a rebuttal, Chan et al. (2007) pointed out that the age distribution of SARS patients and the controls used by Tang et al. (2007) were not matched, and that there were significant genotypic differences between neonates, university students, and elderly control populations suggesting age-related selection. Chan et al. (2007) also noted laboratory and statistical analysis concerns in the study of Zhi et al. (2007).
Li et al. (2008) genotyped SNPs in CLEC4M and other genes in the C-type lectin cluster in 181 Chinese SARS patients and 172 controls from an ethnically matched population and found no significant association with disease predisposition or prognosis. However, they detected a population stratification of the CLEC4M variable number tandem repeat (VNTR) alleles in a sample of 1,145 Han Chinese from different parts of China (northeast, south, and southwest). Analysis extended to 742 individuals from 7 ethnic minorities showed that those located along the Silk Road in northwestern China, where there is significant admixture with the European gene pool, had a low level of homozygosity, similar to European populations. Li et al. (2008) concluded that there is no SARS predisposition allele in the lectin gene cluster at chromosome 19p13.3, and that the previously reported association with polymorphisms in the CLEC4M neck region may be due to population stratification.
The innate immunity system constitutes the first line of host defense against pathogens. Two closely related innate immunity genes, CD209 and CD209L, directly recognize a cluster of pathogens, including bacteria, viruses, and parasites. To explore the extent to which pathogens have exerted selective pressure on these innate immunity genes, Barreiro et al. (2005) resequenced them in a group of samples from sub-Saharan Africa, Europe, and East Asia. Moreover, variation in the number of repeats in the neck region was defined in the entire Human Genome Diversity Panel for both genes. The results, which were based on diversity levels, neutrality tests, population genetic distances, and neck-region length variation, provided genetic evidence that CD209 has been under a strong selective constraint that prevents accumulation of any amino acid changes, whereas CD209L variability has most likely been shaped by the action of balancing selection in non-African populations. In addition, the data pointed to the neck region as the functional target of such selective pressures: CD209 presented a constant size in the neck region populationwide, whereas CD209L presented an excess of length variation, particularly in non-African populations. An additional interesting observation came from the coalescent-based CD209 gene tree, whose binary typology and time depth (approximately 2.8 million years ago) were compatible with an ancestral population structure in Africa.
Using a mouse model of food allergy, Zhou et al. (2010) found that mice pretreated with bovine serum albumin (BSA) with 51 molecules of mannoside (Man51-BSA) plus cholera toxin via oral delivery exhibited reduced BSA-induced anaphylaxis compared with mice pretreated with BSA plus cholera toxin. Man51-BSA selectively targeted lamina propria DCs (LPDCs) expressing Signr1, a mouse homolog of CD209 and CLEC4M, and induced Il10 (124092), but not Il6 (147620) or Il12 p70 (see 161560). Man51-BSA induced the same effects in Il10-GFP knockin (tiger) mice. Interaction of Man51-BSA with Signr1 resulted in the generation of Cd4-positive type-1 regulatory-like (Tr1-like) cells that expressed Il10 and Ifng (147570) in a Signr1- and Il10-dependent manner, but not Cd4-positive/Cd25 (IL2RA; 147730)-positive/Foxp3 (300292)-positive regulatory T cells. Tolerance could be transferred by the Tr1-like cells. Zhou et al. (2010) proposed that sugar-modified antigens may be useful in inducing tolerance by targeting Signr1 homologs and LPDCs.
Barreiro, L. B., Patin, E., Neyrolles, O., Cann, H. M., Gicquel, B., Quintana-Murci, L. The heritage of pathogen pressures and ancient demography in the human innate-immunity CD209/CD209L region. Am. J. Hum. Genet. 77: 869-886, 2005. [PubMed: 16252244] [Full Text: https://doi.org/10.1086/497613]
Bashirova, A. A., Geijtenbeek, T. B. H., van Duijnhoven, G. C. F., van Vliet, S. J., Eilering, J. B. G., Martin, M. P., Wu, L., Martin, T. D., Viebig, N., Knolle, P. A., KewalRamani, V. N., van Kooyk, Y., Carrington, M. A dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN)-related protein is highly expressed on human liver sinusoidal endothelial cells and promotes HIV-1 infection. J. Exp. Med. 193: 671-678, 2001. [PubMed: 11257134] [Full Text: https://doi.org/10.1084/jem.193.6.671]
Chan, K. Y. K., Chan, V. S. F., Chen, Y., Yip, S.-P., Lin, C.-L. S., Khoo, U.-S. Reply to 'Lack of support for an association between CLEC4M homozygosity and protection against SARS coronavirus infection'. (Letter) Nature Genet. 39: 694-696, 2007.
Chan, V. S. F., Chan, K. Y. K., Chen, Y., Poon, L. L. M., Cheung, A. N. Y., Zheng, B., Chan, K.-H., Mak, W., Ngan, H. Y. S., Xu, X., Screaton, G., Tam, P. K. H., Austyn, J. M., Chan, L.-C., Yip, S.-P., Peiris, M., Khoo, U.-S., Lin, C.-L. S. Homozygous L-SIGN (CLEC4M) plays a protective role in SARS coronavirus infection. Nature Genet. 38: 38-46, 2006. [PubMed: 16369534] [Full Text: https://doi.org/10.1038/ng1698]
Feinberg, H., Mitchell, D. A., Drickamer, K., Weis, W. I. Structural basis for selective recognition of oligosaccharides by DC-SIGN and DC-SIGNR. Science 294: 2163-2166, 2001. [PubMed: 11739956] [Full Text: https://doi.org/10.1126/science.1066371]
Gardner, J. P., Durso, R. J., Arrigale, R. R., Donovan, G. P., Maddon, P. J., Dragic, T., Olson, W. C. L-SIGN (CD 209L) is a liver-specific capture receptor for hepatitis C virus. Proc. Nat. Acad. Sci. 100: 4498-4503, 2003. [PubMed: 12676990] [Full Text: https://doi.org/10.1073/pnas.0831128100]
Jeffers, S. A., Tusell, S. M., Gillim-Ross, L., Hemmila, E. M., Achenbach, J. E., Babcock, G. J., Thomas, W. D., Jr., Thackray, L. B., Young, M. D., Mason, R. J., Ambrosino, D. M., Wentworth, D. E., DeMartini, J. C., Holmes, K. V. CD209L (L-SIGN) is a receptor for severe acute respiratory syndrome coronavirus. Proc. Nat. Acad. Sci. 101: 15748-15753, 2004. [PubMed: 15496474] [Full Text: https://doi.org/10.1073/pnas.0403812101]
Lauer, G. M., Walker, B. D. Medical progress: hepatitis C virus infection. New Eng. J. Med. 345: 41-52, 2001. [PubMed: 11439948] [Full Text: https://doi.org/10.1056/NEJM200107053450107]
Li, H., Tang, N. L.-S., Chan, P. K. S., Wang, C.-Y., Hui, D. S.-C., Luk, C., Kwok, R., Huang, W., Sung, J. J.-Y., Kong, Q.-P., Zhang, Y.-P. Polymorphisms in the C-type lectin genes cluster in chromosome 19 and predisposition to severe acute respiratory syndrome coronavirus (SARS-CoV) infection. J. Med. Genet. 45: 752-758, 2008. [PubMed: 18697825] [Full Text: https://doi.org/10.1136/jmg.2008.058966]
Li, W., Moore, M. J., Vasilieva, N., Sui, J., Wong, S. K., Berne, M. A., Somasundaran, M., Sullivan, J. L., Luzuriaga, K., Greenough, T. C., Choe, H., Farzan, M. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 426: 450-454, 2003. [PubMed: 14647384] [Full Text: https://doi.org/10.1038/nature02145]
Soilleux, E. J., Barten, R., Trowsdale, J. Cutting edge: DC-SIGN; a related gene, DC-SIGNR; and CD23 form a cluster on 19p13. J. Immun. 165: 2937-2942, 2000. [PubMed: 10975799] [Full Text: https://doi.org/10.4049/jimmunol.165.6.2937]
Tang, N. L.-S., Chan, P. K.-S., Hui, D. S.-C., To, K.-F., Zhang, W., Chan, F. K. L., Sung, J. J.-Y., Lo, Y. M. D. Lack of support for an association between CLEC4M homozygosity and protection against SARS coronavirus infection. Nature Genet. 39: 691-692, 2007. [PubMed: 17534354] [Full Text: https://doi.org/10.1038/ng0607-691]
Yokoyama-Kobayashi, M., Yamaguchi, T., Sekine, S., Kato, S. Selection of cDNAs encoding putative type II membrane proteins on the cell surface from a human full-length cDNA bank. Gene 228: 161-167, 1999. [PubMed: 10072769] [Full Text: https://doi.org/10.1016/s0378-1119(99)00004-9]
Zhi, L., Zhou, G., Zhang, H., Zhai, Y., Yang, H., Zhang, F., Wang, S., Wei, M., Cao, W., He, F. Lack of support for an association between CLEC4M homozygosity and protection against SARS coronavirus infection. Nature Genet. 39: 692-694, 2007. [PubMed: 17534355] [Full Text: https://doi.org/10.1038/ng0607-692]
Zhou, Y., Kawasaki, H., Hsu, S.-C., Lee, R. T., Yao, X., Plunkett, B., Fu, J., Yang, K., Lee, Y. C., Huang, S.-K. Oral tolerance to food-induced systemic anaphylaxis mediated by the C-type lectin SIGNR1. Nature Med. 16: 1128-1133, 2010. [PubMed: 20835248] [Full Text: https://doi.org/10.1038/nm.2201]