TAILIEUCHUNG - Báo cáo khoa học: A functional polymorphism at the transcriptional initiation site in b2-glycoprotein I (apolipoprotein H) associated with reduced gene expression and lower plasma levels of b2-glycoprotein I

Humanb2 -glycoprotein I (b2 GPI), also known as apolipo-protein H, has been implicated in haemostasis and the pro-duction ofanti-phospholipid antibodies. There is a wide range ofinterindividual variation in b2GPI plasma levels that is thought to be under genetic control, but itsmolecular basis remains unknown. To understand the genetic basis of b2GPI variation, we analyzed the 5¢ flanking region ofthe b2GPIgene for mutation detection by DHPLC and identi-fied a point mutation at the transcriptional initiation site ()1CfiA) with a carrier frequency of . . | Eur. J. Biochem. 270 230-238 2003 FEBS 2003 doi A functional polymorphism at the transcriptional initiation site in p2-glycoprotein I apolipoprotein H associated with reduced gene expression and lower plasma levels of b2-glycoprotein I Haider Mehdi1 Susan Manzi2 Purnima Desai1 Qi Chen1 Cara Nestlerode1 Franklin Bontempo2 Stephen C. Strom3 Reza Zarnegar3 and M. Ilyas Kamboh1 1 Department of Human Genetics Graduate School of Public Health department of Medicine and 3Department of Pathology University of Pittsburgh USA Human p2-glycoprotein I P2GPI also known as apolipoprotein H has been implicated in haemostasis and the production of anti-hhoshholipid anlioddies. Three is a wide range of intrrinpipidual variation nn P2GPI plasma levels that is thought to be under genetic control but its molecular basis remains unknown. To understand the genetic basis of P2GPI variation we analyzed the 5 flanking region of the b2GPI gene for mutation detection by DHPLC and identified a point mutation at the transcriptional initiation site -1CfiA with a carrier frequency of . The mutation was associated with significantly lower P2GPI plasma levels P and low occurrence of nnti-phospholipid antibodies in lupus patients antibody-positive group vs. in the antibody-negative group P . Northern blot analysis confirmed that the - 1CfiAmutation 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 -1CfiA mutation disrupts the binding for crude hepatic nuclear extracts and purified TFIID. These results suggest that the substitution of C with A tit the b2GPI transcriptional initiation site is a causative mutation that affects its gene expression at the transcriptional level and ultimately P2GPI plasma levels and the occurrence ofanti-phospholipid antibodies. Keywords p2-glycoprotein I apolipoprotein H anti-phospholipid .

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