Disease relevance of THBS4

• Furthermore, several variables appeared to modify the effect of THBS4 on MI, including waist-to-hip ratio, diabetes mellitus, and hypertension [1].
• A missense variant of thrombospondin 4 (A387P) showed the strongest association, with an adjusted odds ratio for myocardial infarction of 1.89 (P=0.002 adjusted for covariates) for individuals carrying the P allele [2].
• Thrombospondin-4 Ala387Pro polymorphism is not associated with vascular function and risk of coronary heart disease in US men and women [3].

High impact information on THBS4

• A new member of the thrombospondin gene family, designated thrombospondin-4, has been identified in the Xenopus laevis genome [4].
• Northern blot analysis of human tissues reveals high levels of thrombospondin-4 expression in heart and skeletal muscle, low levels in brain, lung and pancreas and undetectable levels in the placenta, liver and kidney [4].
• High-throughput genomic technology identified an association between a single nucleotide polymorphism (SNP), a proline (P387) rather than the predominant alanine (A387) at position 387 in thrombospondin-4 (TSP-4) and premature myocardial infarction [5].
• Integrin alpha(M)beta2 was identified as the TSP-4 receptor mediating these responses, and the 3 epidermal growth factor (EGF)-like domains of TSP-4 harboring the SNPs interacted with the alpha(M)I-domain [5].
• Additionally, cells adherent to P387 TSP-4 variant released 4-fold more H2O2 and secreted 2-fold more interleukin 8 (IL-8) as compared with the A387 [5].

Biological context of THBS4

• In TSP-4, the P387 form acquired an additional Ca2+ binding site absent in the A387 form [6].
• RESULTS: In the replication population, no significant association was found between THBS4 genotype and MI (P =.41) with univariate analysis [1].
• Hypermethylation of the putative tumor suppressor genes BCL7a (in 48% of CTCL samples), PTPRG (27%), and thrombospondin 4 (52%) was confirmed and demonstrated to be associated with transcriptional downregulation [7].
• Transfection of mouse NIH3T3 fibroblasts or C2C12 myoblasts with a full-length human thrombospondin-4 cDNA results in the expression of a polypeptide with a reduced molecular weight of 140,000 [8].
• Alignment of the amino acid sequences of the Drosophila TSP with human TSP1-TSP4 and COMP demonstrated a high degree of homology between the four Type II repeats, seven Type III repeats, and C-terminal domain [9].

Anatomical context of THBS4

• In addition, profound differences in the function of the thrombospondin-4 SNP variants have been identified with respect to their capacity to support endothelial cell adhesion and proliferation [10].
• The C-terminal peptide of thrombospondin-4 stimulates erythroid cell proliferation [11].
• The presence of multiple E-box sequence motifs is consistent with thrombospondin-4 expression in muscle and bone tissue [12].
• Pre-incubation of the low molecular weight fractions from supernatants of EPO-treated umbilical cord endothelial cells (HUVEC) with antibodies against the C-terminal residues of TSP-1,2 and TSP-4 decreased the erythroid cell stimulating activity [11].
• Mechanism and effect of thrombospondin-4 polymorphisms on neutrophil function [5].

Associations of THBS4 with chemical compounds

• Atomic absorption spectroscopy demonstrated that the thrombospondin-4 constructs bind seven less calcium than the thrombospondin-2 construct at 0.6 mM CaCl2 [13].
• These data indicate that thrombospondin-4 is a pentameric protein that binds to heparin and calcium [8].
• Thus, alpha(M)beta2 plays a central role in proinflammatory activities of TSP-4 (P387) and may contribute to the prothrombotic phenotype associated with this variant [5].
• Thrombospondin-4 (TSP-4), a large pentameric glycoprotein of the extracellular matrix, has been described as a neurite outgrowth-promoting molecule [14].
• BACKGROUND: In a recent large-scale genetic association study, a single nucleotide polymorphism in the thrombospondin-4 (TSP-4) gene, resulting in a proline-for-alanine substitution at position 387, was associated with a significantly increased risk for premature atherosclerosis [15].

Other interactions of THBS4

• The THBS2 and THBS4 associations have since been replicated [16].
• The disease-associated polymorphisms lead to single amino acid changes in TSP-4 (A387P) and TSP-1 (N700S) [6].
• In the human genome, the TSP-1, TSP-3, TSP-4 and TSP-5 genes lie within paralogous regions that provide insight into the ancestral genomic context of vertebrate TSPs [17].

Analytical, diagnostic and therapeutic context of THBS4

• Titrations of the spectra demonstrated lower cooperativity and affinity for binding of calcium to thrombospondin-4 compared with thrombospondin-2 [13].
• In 2 mM CaCl2, the near UV circular dichroism spectra of thrombospondin-2, but not thrombospondin-4, contain a positive band at 292 nm that disappears upon calcium chelation [13].
• Electron microscopy indicates that thrombospondin-4 is composed of five subunits with globular domains at each end [8].
• Recombinant thrombospondin-4 has been purified from the culture supernatant by heparin-Sepharose and anti-thrombospondin-4 antibody-Affi-gel affinity chromatography [8].
• The TSP-4 A387P polymorphism was determined by PCR and PCR-RFLP (restriction-fragment-length polymorphism) analysis [18].

References