Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P02749 (beta2-glycoprotein I)
 836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human beta2-glycoprotein I (beta2GPI), also known as apolipoprotein H, has been implicated in haemostasis and the production of anti-phospholipid antibodies. There is a wide range of interindividual variation in beta2GPI plasma levels that is thought to be under genetic control, but its molecular basis remains unknown. To understand the genetic basis of beta2GPI variation, we analyzed the 5' flanking region of the beta2GPI gene for mutation detection by DHPLC and identified a point mutation at the transcriptional initiation site (-1C-->A) with a carrier frequency of 12.1%. The mutation was associated with significantly lower beta2GPI plasma levels (P < 0.0001) and low occurrence of anti-phospholipid antibodies in lupus patients (4.8% antibody-positive group vs. 16.6% in the antibody-negative group; P = 0.019). Northern blot analysis confirmed that the -1C-->A mutation was associated with lower mRNA levels and it reduced the reporter (luciferase) gene expression by twofold. Electrophoretic gel mobility shift assay (EMSA) revealed that the -1C-->A mutation disrupts the binding for crude hepatic nuclear extracts and purified TFIID. These results suggest that the substitution of C with A at the beta2GPI transcriptional initiation site is a causative mutation that affects its gene expression at the transcriptional level and ultimately beta2GPI plasma levels and the occurrence of anti-phospholipid antibodies.
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PMID:A functional polymorphism at the transcriptional initiation site in beta2-glycoprotein I (apolipoprotein H) associated with reduced gene expression and lower plasma levels of beta2-glycoprotein I. 1260 74

This study characterized the human apolipoprotein H [APOH; beta(2)-glycoprotein I (beta(2)GPI)] promoter and its variants by in vitro functional experiments and investigated their relationship with human plasma beta(2)GPI levels. We examined the individual effects of 12 APOH promoter single nucleotide polymorphisms in the 5' flanking region of APOH (approximately 1.4 kb) on luciferase activity in COS-1 cells and HepG2 cells and their impact on plasma beta(2)GPI levels in 799 American White people, the DNA binding properties of the APOH promoter using an electrophoretic mobility shift assay in HepG2 cells, the effects of serial deletion analysis of the APOH 5' flanking region in COS-1 and HepG2 cells and cross-species conservation of the APOH promoter sequence. The variant alleles of three single nucleotide polymorphisms (-1219G>A, -643T>C and -32C>A) showed significantly lower luciferase expression (51, 40 and 37%, respectively) as compared with the wild-type allele. The electrophoretic mobility shift assay demonstrated that these three variants specifically bind with protein(s) from HepG2 cell nuclear extracts. Three-site haplotype analysis (-1219G>A, -643T>C and -32C>A) revealed one haplotype carrying -32A (allele frequency = 0.075) to be significantly associated with decreased plasma beta(2)GPI levels (P < 0.001). Deletion analysis localized the core APOH promoter to approximately 160 bp upstream of ATG codon with the presence of critical cis-acting elements between -166 and -65. Cross-species conservation analysis of the APOH promoters of seven species indicated that basic promoter elements are highly conserved across species. In conclusion, we have characterized the functional promoter of APOH and identified functional variants that affect the transcriptional activity of the APOH promoter.
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PMID:Functional and genetic characterization of the promoter region of apolipoprotein H (beta2-glycoprotein I). 2008 41