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The Human Integrin  3 Gene Is 63 kb and Contains a 5'-UTR Sequence Regulating Expression
Calvin C. Wilhide,
Ying Jin,
Qingbin Guo,
Lu Li,
Su-Xia Li,
Edwin Rubin, and
Paul F. Bray
From the Division of Hematology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD; and the Lawrence Berkeley Laboratories, Berkeley, CA.
The human blood platelet fibrinogen receptor, integrin  IIb 3 (glycoprotein IIb-IIIa) is an archetypal member of the integrin family of adhesive molecules and is the only integrin encoded by genes physically linked in the genome. Because studies on the normal and abnormal expression of any gene require a thorough understanding of its organization, the initial goals of the current study were to determine the size and complete the genomic organization for the 3 gene. We now report the isolation of the entire 3 gene in a single P1 plasmid and for the first time have linked the first and second exons on a contiguous fragment of DNA. Using pulsed-field gel analysis, we determined the full size of the 3 gene to be 63 kb and show a large (16.7 kb) first intron; based on this information, we propose a uniform numbering system for the 3 exons. We have completed the 5' genomic structure and generated a long-range restriction map. The promoter and the 5' end of the first intron were found to have approximately 50% sequence identity with a region of the avian 3 gene known to possess functional transcriptional activity. Analysis of three different homologous regions led to the identification of a sequence in the 5'-UTR of the human gene, CCGCGGGAGG, which shares 90% identity with the avian gene and which bound nuclear proteins in DNaseI and electrophoretic mobility shift assay studies. Mutating this sequence caused a 2.6-fold reduction in reporter gene activity. In these studies we have (1) determined the full length and 5' organization of the 3 gene, (2) identified a large region of homology between the 5' regions of the avian and human genes, and (3) identified a sequence in the 5'-UTR that augments gene expression. Knowing the genomic structure of 3 has permitted the uncovering of new mechanisms of mutagenesis causing Glanzmann thrombasthenia (Jin et al, J Clin Invest 98:1745, 1996), and our findings will be valuable for such genetic analyses as well as for studies on the transcriptional regulation of 3 and other integrin genes.
Blood, Vol. 90 No. 10 (November 15), 1997:
pp. 3951-3961
© 1997 by The American Society of Hematology.
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