動脈硬化と血栓形成に関わるプラスミノゲン·アポリボプロテイン(a)遺伝子ファミリーの分子病態と遺伝子診断

摘要

Plasminogen is a key proenzyme of plasmin in the fibrinolytic and thrombolytic systems, the deficiency of which leads to a mild thrombotic tendency. Plasminogen binds to fibrin as well as to the surface of en-dothelial cells and monocytes/macrophages, where it is activated to plasmin. Individuals with dysplas-minogenemia were analyzed by a combination of PCR and restriction digestion. Among 125 unrelated families, an Ala601-Thr mutation accounted for about 94% of cases, while a Val355-Phe mutation was found in four unrelated families. A new mutation, Asp676-Asn, has been identified in two cases. To facilitate the rapid genetic diagnosis of dysplasminogenemia, we also developed a method that combines an amplification refractory mutation system and rapid automated capillary electrophoresis. Apolipopro-tein (a) [apo (a) ] is a protein component of lipoprotein (a), high plasma levels of which constitute a risk factor for atherosclerotic thromboembolic disease. Since apo (a) is very similar to plasminogen in terms of amino acid sequence, it inhibits plasmin generation by competing with plasminogen's binding to fibrin and endothelial cells. Although the plasma Lp (a) concentration roughly correlates with the size and number of Kringle 4 repeats of apo (a), a significant variation in the Lp (a) level exists among individuals having the same inform. We subclassified the apo (a) gene into four types (A-D) by polymorphisms in its 5'-flanking region. We also measured plasma Lp (a) concentrations in vivo and examined expression of the gene by in vitro assay. Homozygotes of type C had higher Lp (a) levels than those of type D, and the relative expression of type C was higher than that of type D in vitro. Thus, Lp (a)^ concentrations in human plasma are predetermined at the genetic level by extensive polymorphisms in both the 5'-alleles and the numbers of Kringle 4 repeats.