Alternative titles; symbols
HGNC Approved Gene Symbol: SDC3
Cytogenetic location: 1p35.2 Genomic coordinates (GRCh38): 1:30,869,466-30,909,735 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p35.2 | {Obesity, association with} | 601665 | Autosomal dominant; Autosomal recessive; Multifactorial | 3 |
Heparan sulfate proteoglycans are ubiquitous components of the plasma membranes of mammalian cells. Some of these are integral membrane proteoglycans including those with transmembrane core proteins and those that are attached to membranes by glycosylphosphatidylinositol (GPI) membrane anchors. Carey et al. (1992) isolated a cDNA clone encoding a membrane proteoglycan core protein from a neonatal rat Schwann cell cDNA library by screening with an oligonucleotide based on a conserved sequence in cDNAs coding for previously described proteoglycan core proteins. Although there was a high degree of similarity with the transmembrane and cytoplasmic domains of previously described proteoglycans, the new protein had a unique extracellular domain sequence. Northern blots showed a distribution of a single 5.6-kb mRNA in Schwann cells, neonatal rat brain, rat heart, and rat smooth muscle cells. Antibodies raised against the protein demonstrated immunoreactivity in tissues from peripheral nerve newborn rat brain, heart, aorta, etc. Because of its isolation initially from neural cells and its high expression in nervous tissue, Carey et al. (1992) suggested the name N-syndecan for this heparan sulfate proteoglycan.
By screening a human fetal brain cDNA library with a fragment of the ectodomain of human SDC3, followed by ligation of overlapping clones, Berndt et al. (2001) obtained a full-length SDC3 cDNA. The deduced 443-amino acid protein contains a large extracellular domain, followed by a glycine-rich transmembrane domain and a short cytoplasmic tail that contains the constant and variable regions characteristic of syndecans. The extracellular domain has 8 glycosaminoglycan attachment sites arranged in 2 clusters, and the intracellular domain has a PDZ domain-interacting motif and 4 conserved tyrosine residues. RNA dot blot analysis detected highest SDC3 expression in adult and fetal brain, adrenal gland, and spleen. Strong expression was detected in almost all specific brain regions examined except pituitary gland. Expression was also found in stomach, colon, rectum, and aorta. SDC3 localized to the membrane in transiently transfected cells.
Berndt et al. (2001) found that transfection of SDC3 resulted in the formation of long filopodia-like structures, microspikes, and varicosities in several cell lines. The actin cytoskeleton was reorganized, and actin colocalized with SDC3 in the cellular extensions and at the cell periphery. The development of the phenotype depended on the presence of cell surface sugar chains, as transfected glycosaminoglycan-deficient Chinese hamster ovary cells did not show these structural changes, nor did wildtype cells treated with heparin, which would compete with the sugar chains of expressed SDC3.
Bobardt et al. (2003) demonstrated that syndecans, including SDC3, can function as in trans HIV receptors via binding of HIV-1 gp120 to the syndecan heparan sulfate chains. Flow cytometric analysis demonstrated SDC expression on endothelial cells. HIV bound to SDC on endothelial cell lines maintained its infectivity for at least 1 week, compared with less than 1 day for unbound virus. Bobardt et al. (2003) suggested that SDC-rich endothelial cells lining the vasculature can provide a microenvironment that boosts HIV replication in T cells.
De Witte et al. (2007) reported that SDC3 captured HIV-1 on dendritic cells (DCs) through HIV-1 gp120, stabilized the captured virus, enhanced DC infection in cis, and promoted transmission to T cells. Heparinase III removal of heparan sulfate or SDC3 small interfering RNA partially inhibited HIV-1 transmission by immature DCs, whereas neutralization of both SDC3 and the C-type lectin receptor, DCSIGN (CD209; 604672), completely abrogated HIV-1 capture and subsequent transmission.
Spring et al. (1994) showed that in the mouse the Synd3 gene maps to chromosome 4 near the Lmyc gene. Curiously, in the mouse, the Synd1 gene (186355) is on chromosome 12 near Nmyc, Synd2 is on chromosome 15 close to Myc, and Synd4 is on chromosome 2 where Bmyc is located. The physical relationship between members of these 2 gene families appears to be ancient and conserved after the 2 genome duplications thought to have occurred during vertebrate evolution. Presumably, the SYND3 gene in the human is located on 1p in the same region as LMYC (164850), which maps to 1p32.
Ha et al. (2006) tested the hypothesis that SNPs in SDC3 are associated with obesity in the Korean population. They conducted a population-based cohort study consisting of 229 control and 245 study subjects and a second independent study consisting of 192 control and 115 study subjects. They found association of 2 nonsynonymous single-nucleotide polymorphisms (SNPs), T271I (186357.0001) and V150I (186357.0002), with obesity (P less than 0.0001). The results were confirmed in the second independent study group. Haplotype analysis also revealed strong association with obesity (chi square = 76.92, P less than 0.000001). Ha et al. (2006) concluded that there are ethnic differences in SDC3 polymorphisms, and that the polymorphisms are strongly associated with obesity.
Reizes et al. (2001) found that transgenic expression in the hypothalamus of Sdc1 produced mice with hyperphagia and maturity-onset obesity resembling mice with reduced action of alpha-melanocyte-stimulating hormone (alpha-MSH; see 155555). Through their heparan sulfate chains, syndecans potentiate the action of agouti-related protein (602311) and agouti signaling protein (600201), endogenous inhibitors of alpha-MSH. In wildtype mice, Sdc3 was expressed in hypothalamic regions that control energy balance. Food deprivation increased hypothalamic Sdc3 levels several-fold. Sdc3-null mice, which otherwise appeared normal, responded to food deprivation with markedly reduced reflex hyperphagia. Reizes et al. (2001) proposed that oscillation of hypothalamic SDC3 levels physiologically modulates feeding behavior.
Strader et al. (2004) demonstrated that Sdc3 -/- mice are lean and resistant to diet-induced obesity compared to wildtype mice. On a high-fat diet, Sdc3-null mice exhibited a partial resistance to obesity due to reduced food intake in males and increased energy expenditure in females relative to that of wildtype mice. The Sdc3-null mice on a high-fat diet accumulated less adipose mass and showed better glucose tolerance than wildtype controls.
Cornelison et al. (2004) reported that Sdc3 -/- mice exhibited a novel form of muscular dystrophy characterized by impaired locomotion, fibrosis, and hyperplasia of myonuclei and satellite cells. A high percentage of regenerating myofibers was observed both in uninjured muscle and after induced regeneration. Explanted mutant satellite cells mislocalized Myod (159970), differentiated aberrantly, and exhibited a general increase in overall tyrosine phosphorylation.
In a population-based cohort study consisting of 245 obese Korean subjects and 229 age- and gender-matched controls, Ha et al. (2006) observed a correlation of the TT genotype of a nonsynonymous SNP in exon 3 of the SDC3 gene, rs2282440, with obesity (601665) (P = 0.0004). The results were confirmed in a second independent study group. The frequency of the CC genotype in the controls was more than 2-fold that seen in obese subjects (21.0% vs 9.8%, respectively), suggesting that the CC genotype may confer resistance to obesity in the Korean population. The C-to-T transition that constitutes rs2282440 results in a thr-to-ile substitution at codon 271 of syndecan-3 (T271I).
In a population-based cohort study consisting of 245 obese Korean subjects and 229 age- and gender-matched controls, Ha et al. (2006) observed a correlation of the CC genotype of a nonsynonymous SNP in exon 2 of the SDC3 gene, rs2491132, with obesity (601665) (P less than 0.0001). The results were confirmed in a second independent study group. The frequency of the TT genotype of rs2491132 in the controls was more than 5 times higher than in obese subjects (6.6% vs 1.2%, respectively). The C-to-T transition that constitutes rs2491132 results in a val-to-ile substitution at codon 150 of syndecan-3 (V150I).
Berndt, C., Casaroli-Marano, R. P., Vilaro, S., Reina, M. Cloning and characterization of human syndecan-3. J. Cell. Biochem. 82: 246-259, 2001. [PubMed: 11527150] [Full Text: https://doi.org/10.1002/jcb.1119]
Bobardt, M. D., Saphire, A. C. S., Hung, H.-C., Yu, X., Van der Schueren, B., Zhang, Z., David, G., Gallay, P. A. Syndecan captures, protects, and transmits HIV to T lymphocytes. Immunity 18: 27-39, 2003. [PubMed: 12530973] [Full Text: https://doi.org/10.1016/s1074-7613(02)00504-6]
Carey, D. J., Evans, D. M., Stahl, R. C., Asundi, V. K., Conner, K. J., Garbes, P., Cizmeci-Smith, G. Molecular cloning and characterization of N-syndecan, a novel transmembrane heparan sulfate proteoglycan. J. Cell Biol. 117: 191-201, 1992. [PubMed: 1556152] [Full Text: https://doi.org/10.1083/jcb.117.1.191]
Cornelison, D. D. W., Wilcox-Adelman, S. A., Goetinck, P. F., Rauvala, H., Rapraeger, A. C., Olwin, B. B. Essential and separable roles for syndecan-3 and syndecan-4 in skeletal muscle development and regeneration. Genes Dev. 18: 2231-2236, 2004. [PubMed: 15371336] [Full Text: https://doi.org/10.1101/gad.1214204]
de Witte, L., Bobardt, M., Chatterji, U., Degeest, G., David, G., Geijtenbeek, T. B. H., Gallay, P. Syndecan-3 is a dendritic cell-specific attachment receptor for HIV-1. Proc. Nat. Acad. Sci. 104: 19464-19469, 2007. [PubMed: 18040049] [Full Text: https://doi.org/10.1073/pnas.0703747104]
Ha, E., Kim, M.-J., Choi, B.-K., Rho, J.-J., Oh, D.-J., Rho, T.-H., Kim, K.-H., Lee, H. J., Shin, D.-H., Yim, S. V., Baik, H. H., Chung, J.-H., Kim, J. W. Positive association of obesity with single nucleotide polymorphisms of syndecan 3 in the Korean population. J. Clin. Endocr. Metab. 91: 5095-5099, 2006. [PubMed: 17018662] [Full Text: https://doi.org/10.1210/jc.2005-2086]
Reizes, O., Lincecum, J., Wang, Z., Goldberger, O., Huang, L., Kaksonen, M., Ahima, R., Hinkes, M. T., Barsh, G. S., Rauvala, H., Bernfield, M. Transgenic expression of syndecan-1 uncovers a physiological control of feeding behavior by syndecan-3. Cell 106: 105-116, 2001. [PubMed: 11461706] [Full Text: https://doi.org/10.1016/s0092-8674(01)00415-9]
Spring, J., Goldberger, O. A., Jenkins, N. A., Gilbert, D. J., Copeland, N. G., Bernfield, M. Mapping of the syndecan genes in the mouse: linkage with members of the Myc gene family. Genomics 21: 597-601, 1994. [PubMed: 7959737] [Full Text: https://doi.org/10.1006/geno.1994.1319]
Strader, A. D., Reizes, O., Woods, S. C., Benoit, S. C., Seeley, R. J. Mice lacking the syndecan-3 gene are resistant to diet-induced obesity. J. Clin. Invest. 114: 1354-1360, 2004. Note: Erratum: J. Clin. Invest. 114: 1686 only, 2004. [PubMed: 15520868] [Full Text: https://doi.org/10.1172/JCI20631]