Plasminogen with type-I mutation is polymorphic in the Japanese population

Abstract

A functionally inactive plasminogen (PLG) variant designated as PLG M5 is polymorphic in the Japanese population and has a feature common to PLG with type-I mutation that has a codon 601 missense mutation in exon 15 (GCT for Ala-->ACT for Thr). This study was conducted to clarify whether the type-I mutation of PLG is present in PLG M5 and polymorphic in the Japanese population. Direct sequencing of the amplified DNA from the PLG gene in a heterozygote for PLG M5 revealed that the sequence of the exon 15 in the gene for PLG M5 is identical with that in the PLG gene with type-I mutation. In addition, the amplified DNA from the PLG gene in 12 heterozygotes for PLG M5 reacted with the probe for the type-I mutation in dot blot hybridization with an allele-specific oligonucleotide probe. The heterozygote for PLG with type-I mutation was found in 2.2% of 360 unrelated healthy subjects. These data indicate that the type-I mutation of PLG is present in PLG M5 and polymorphic in the Japanese population. The data also suggest that the PLG M5 is identical with PLG Tochigi and Kagoshima.

Plasminogen deficiency causes severe thrombosis but is compatible with development and reproduction.

“…The development of fibrin deposits in Plg-/-mice is consistent with the severe thrombotic problems reported in patients identified with dysplasminogenemia (Aoki et al 1978;Ichinose et al 1991;Kikuchi et al 1992;Robbins 1992;Azuma et al 1993) and hypoplasminogenemia (Lottenberg et al 1985;Girolami et al 1986;Mannucci et al 1986;Dolan et al 1988;Patrassi et al 1993), which include recurring venous thrombosis, pulmonary hypertension, retinopathy, and stroke. However, the total deficit of Pig established in transgenic mice is distinct from any known Plg disorder in human patients.…”

“…Interestingly, simple heterozygosity for either Plg deficiency (with half-normal Plg activity and antigen) or dysplasminogenemia (with half-normal Plg activity but normal antigen) appears to be associated with thrombotic tendency requiring clinical treatment. However, other factors, such as infection, injury, or vascular disease, are likely to contribute to this tendency, as only a subset of heterozygotes, even within the same family, suffer from thrombosis (Aoki et al 1978;Girolami et al 1986;Dolan et al 1988;Kikuchi et al 1992;Robbins 1992;Azuma et al 1993;Patrassi et al 1993). Remarkably, one form of dysplasminogenemia (type-l, Ala 6~ ~ Thr) occurs with an estimated gene frequency of -2% in the Japanese population (Kikuchi et al 1992), but few homozygous patients (-10% residual activity; Aoki et al 1978) have ever been identified (Aoki et al 1978;Ichinose et al 1991;Kikuchi et al 1992).…”

“…However, considerable uncertainty still remains as to the roles of Plg outside fibrinolysis because other PAs of unknown biological significance have been identified, including plasma kallikrein, (Kluft et al 1987), factor XIIa (Goldsmith et al 1978), and factor XIa (Mandle and Kaplan 1979). In addition, although Plg disorders are encountered frequently in some populations (Ichinose et al 1991;Kikuchi et al 1992), no homozygotes with total Plg deficiency have ever been documented. Finally, potent biological activities have been associated with the noncatalytic portions of Plg, including the angiogenesis-and metastasis-suppressing activity of the Plg derivative, angiostatin, which is made up solely of kringle domains (O'Reilly et al 1994).…”

Detection of an Ala601Thr Mutation of Plasminogen Gene in 3 out of 36 Korean Patients with Deep Vein Thrombosis

“…Previously, by isoelectric focusing electrophoresis, several workers identified a functionally inactive PLG variant designated PLG M5, and demonstrated that PLG Tochigi and PLG Nagoya II are identical and has a feature common to PLG M5 with an Ala601Thr point mutation (11).…”

Isoelectric focusing pattern of plasminogen mutants of patients with hypoplasminogenemia

“…Compound heterozygosity for plg 453N/D correlates with an equal 'mixture' of IEF plg phenotypes A and B, which was previously described as a distinct phenotype and designated AB [10]. Furthermore, it has been shown that dysplasminogenemia due to plg mutation A601T leads to IEF phenotype M5 ( plg Tochigi) [11,12]. Distinct aberrant new IEF band patterns have been also described in three patients with hypoplasminogenemia due to the presence of a K19E mutation in a homozygous or compound heterozygous state [10].…”