MULTIPLE MEMBERS OF THE PLASMINOGEN APOLIPOPROTEIN(A) GENE FAMILY ASSOCIATED WITH THROMBOSIS

Plasminogen and apolipoprotein(a) [apo(a)] are closely related plasma proteins that are associated with hereditary thrombophilia. Low plasminogen levels are found in some patients who developed venous thrombosis, while a population with high plasma concentrations of apo(a) have a higher incidence of arterial thrombosis. Two different genes coding for human apo(a) have been isolated and characterized in order to study and compare these genes with four other closely related genes in the plasminogen-apo(a) gene family. These include the gene coding for plasminogen, two unique plasminogen-related genes, and a gene coding for hepatocyte growth factor. Nucleotide sequence analysis of these genes revealed that the exons and their boundaries of the genes for plasminogen and apo(a), and the plasminogen-related genes, differ only 1-5% in sequence. The types of exon/intron junctions and positions of introns in the molecules are also exactly identical, suggesting that these genes have evolved from an ancestral plasminogen gene via duplication and exon shuffling. By utilizing these results, gene-specific probes have been designed for the analysis of each of the genes in this gene family. The plasminogen and two apo(a) genes were all localized to chromosome 6 by employing the gene-specific primers and genomic DNAs from human-hamster cell hybrids. These data also make it possible to characterize the apo(a) and plasminogen genes in individuals by in vitro amplification.