HGNC Approved Gene Symbol: THBS4
Cytogenetic location: 5q14.1 Genomic coordinates (GRCh38): 5:79,991,332-80,083,287 (from NCBI)
The thrombospondins are a family of extracellular calcium binding proteins involved in cell proliferation, adhesion, and migration.
Thrombospondin 4 (THBS4) was originally identified from a Xenopus stage 45 cDNA library. Lawler et al. (1995) isolated a cDNA for the human THBS4 gene (which they called TSP4) from a heart expression library. Overall, the 961-amino acid predicted protein is 73% identical to the X. laevis sequence; however, the C-terminal 220 residues are over 92% identical. The TSP4 mRNA is approximately 3.4 kb. In contrast to thrombospondin-4 of Xenopus laevis, the human protein contains an RGD (arg-gly-asp) cell-binding sequence in the third type 3 repeat. Transfection of mouse NIH 3T3 fibroblasts or C2C12 myoblasts with a full-length human thrombospondin-4 cDNA resulted in the expression of a polypeptide with a reduced molecular weight of 140,000. In the absence of reducing agent, the expressed protein had an apparent molecular weight of 550,000. Lawler et al. (1995) purified recombinant thrombospondin-4 from the culture supernatant. Electron microscopy indicated that it is composed of 5 subunits with globular domains at each end. Thus, they concluded that thrombospondin-4 is a pentameric protein that binds to heparin and calcium.
Benner et al. (2013) demonstrated in mice that subventricular zone (SVZ)-generated astrocytes express high levels of the secreted homopentameric glycoprotein Thbs4, in contrast to cortical astrocytes, which express low levels of Thbs4. Benner et al. (2013) found that localized photothrombotic/ischemic cortical injury initiates a marked increase in Thbs4(hi) astrocyte production from the postnatal SVZ niche. Tamoxifen-inducible nestin-creER(tm)4 lineage tracing demonstrated that it is these SVZ-generated Thbs4(hi) astrocytes, and not doublecortin (300121)-positive neuroblasts (also generated within the SVZ), that home in on the injured cortex. This robust postinjury astrogenic response required SVZ Notch (190198) activation modulated by Thbs4 via direct Notch1 receptor binding and endocytosis to activate downstream signals, including increased Nfia (600727) transcription factor expression important for glia production. Consequently, Thbs4 homozygous knockout mice showed severe defects in cortical injury-induced SVZ astrogenesis, instead producing cells expressing doublecortin migrating from SVZ to the injury sites. These alterations in cellular responses resulted in abnormal glial scar formation after injury, and significantly increased microvascular hemorrhage into the brain parenchyma of Thbs4-null mice. Taken together, Benner et al. (2013) concluded that their findings have important implications for postinjury applications of endogenous and transplanted NSCs in the therapeutic setting, as well as disease states where Thbs family members have important roles.
The International Radiation Hybrid Mapping Consortium mapped the THBS4 gene to chromosome 5 (SHGC-12514).
McCarthy et al. (2004) analyzed 210 polymorphisms in 111 candidate genes in 352 white subjects with familial premature coronary heart disease and 418 white controls, and found the strongest association with an ala387-to-pro (A387P) variant in THBS4 (p = 0.002).
Eumycetoma is a tumorous fungal infection, typically of the hands or feet, characterized by the infiltration of large numbers of neutrophils. It is caused by Madurella mycetomatis, a pathogen that is abundant in the soil and on the vegetation of Sudan, where the disease is common. Van de Sande et al. (2007) noted that ELISA has shown near universal IgG seropositivity in mycetoma patients and controls from endemic areas, but no seropositivity in European controls, implying that most individuals in endemic areas are exposed to the pathogen, but only a small percentage develop disease. Van de Sande et al. (2007) studied 11 SNPs in genes involved in neutrophil function in 125 Sudanese mycetoma patients and 140 ethnically and geographically matched controls and found significant differences in allele distributions for SNPs in IL8 (146930), IL8RB (146928), TSP4, NOS2 (163730), and CR1 (120620). Serum IL8 was significantly higher in patients compared with controls, while nitrite/nitrate levels were lower in patients and seemed to be associated with delayed wound healing. Van de Sande et al. (2007) concluded that there is a genetic predisposition toward susceptibility to mycetoma.
Benner, E. J., Luciano, D., Jo, R., Abdi, K., Paez-Gonzalez, P., Sheng, H., Warner, D. S., Liu, C., Eroglu, C., Kuo, C. T. Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4. Nature 497: 369-373, 2013. [PubMed: 23615612] [Full Text: https://doi.org/10.1038/nature12069]
Lawler, J., McHenry, K., Duquette, M., Derick, L. Characterization of human thrombospondin-4. J. Biol. Chem. 270: 2809-2814, 1995. [PubMed: 7852353] [Full Text: https://doi.org/10.1074/jbc.270.6.2809]
McCarthy, J. J., Parker, A., Salem, R., Moliterno, D. J., Wang, Q., Plow, E. F., Rao, S., Shen, G., Rogers, W. J., Newby, L. K., Cannata, R., Glatt, K., Topol, E. J. Large scale association analysis for identification of genes underlying premature coronary heart disease: cumulative perspective from analysis of 111 candidate genes. J. Med. Genet. 41: 334-341, 2004. [PubMed: 15121769] [Full Text: https://doi.org/10.1136/jmg.2003.016584]
van de Sande, W. W. J., Fahal, A., Verbrugh, H., van Belkum, A. Polymorphisms in genes involved in innate immunity predispose toward mycetoma susceptibility. J. Immun. 179: 3065-3074, 2007. [PubMed: 17709521] [Full Text: https://doi.org/10.4049/jimmunol.179.5.3065]