Platelet-activating factor acetylhydrolase deficiency. A missense mutation near the active site of an anti-inflammatory phospholipase.

Abstract

Deficiency of plasma platelet-activating factor (PAF) acetylhydrolase is an autosomal recessive syndrome that has been associated with severe asthma in Japanese children. Acquired deficiency has been described in several human diseases usually associated with severe inflammation. PAF acetylhydrolase catalyzes the degradation of PAF and related phospholipids, which have proinflammatory, allergic, and prothrombotic properties. Thus, a deficiency in the degradation of these lipids should increase the susceptibility to inflammatory and allergic disorders. Miwa et al. reported that PAF acetylhydrolase activity is absent in 4% of the Japanese population, which suggests that it could be a common factor in such disorders, but the molecular basis of the defect is unknown. We show that inherited deficiency of PAF acetylhydrolase is the result of a point mutation in exon 9 and that this mutation completely abolishes enzymatic activity. This mutation is the cause of the lack of enzymatic activity as expression in E. coli of a construct harboring the mutation results in an inactive protein. This mutation as a heterozygous trait is present in 27% in the Japanese population. This finding will allow rapid identification of subjects predisposed to severe asthma and other PAF-mediated disorders. ( J. Clin. Invest. 1996. 97:2784-2791.)

Exploratory aspirin resistance trial in healthy Japanese volunteers (J-ART) using platelet aggregation as a measure of thrombogenicity

“…Concerning platelet membrane glycoproteins, it has been reported that genetic polymorphisms of GPIa, 10 GPIba, 11 GPIIIa 12,13 and GPVI 14 influence the efficacy of aspirin or platelet responsiveness. Furthermore, Halushka et al 15 reported the association of platelet aggregation with genetic mutation of COX-1, Papafili et al 16 the association with genetic mutation of COX-2, Higuchi et al 17 the association with genetic mutation of TXA 2 receptors (TP), Stafforini et al 18 the association with genetic mutation of platelet activating factor acetylhydrolase (PAFAH) and Undas et al 19 the association with genetic mutation of coagulation factor XIII (FXIII).…”

Effect of Darapladib on Plasma Lipoprotein-Associated Phospholipase A₂ Activity in Japanese Dyslipidemic Patients, With Exploratory Analysis of a <i>PLA₂G7</i> Gene Polymorphism of Val279Phe

“…The Val279Phe (V279F) homogygous mutation (279FF) is the only polymorphism theoretically resulting in no circulating gene product of Lp-PLA2. 9, 10 The prevalence of 279FF was reported to be 0.4%, 1.2%, and 3% in the Chinese, Korean, and Japanese populations, respectively, 11-13 but this variant is rare in non-Asian populations. 14 In a recent meta-analysis including 79,036 participants in 32 prospective studies, Lp-PLA2 activity and mass each showed continuous associations with risk of CAD, similar in magnitude to that with non-high-density lipoprotein cholesterol and systolic blood pressure.…”

“…9, 10 Jang et al found that the V279F variant in the PLA2G7 gene led to significant loss of enzyme activity in heterozygous subjects and no appreciable enzyme activity in homozygous subjects. The mechanism of the deficiencies of plasma Lp-PLA2 activity were suggested to be due to a loss-of-function mutation (V279F, exon 9, position 994; G3T; G>T) in the Lp-PLA2 gene, because Val-279 conserved in plasma Lp-PLA2 lies between the active site Ser-273 and Asp-296 residues in a region that is critical for proper folding of the enzyme.…”

“…12 It has been reported that the mutant allele was present in 27% of the Japanese population as heterozygotes and in 4% as homozygotes. 10 In contrast, no heterozygous or homozygous deficient subjects were identified in a random North American population 10 and were rare in the Caucasian hapmap samples and absent in the African samples (www.hapmap.org). In addition, some reports showed that Lp-PLA2 activity in the 279VF population was approximately half of that in the 279VV population, and that 279FF completely lacked Lp-PLA2 activity.…”

Study of association between genetic polymorphisms of phospholipase A2 enzymes and Alzheimer's disease

“…Stafforini et al 19 mapped the PLA2G7 gene (PAFAH) to chromosome 6p21.1-p12 and found that it contains 12 exons. Deficiency of plasma platelet-activating factor resulting from a missense mutation (Val279-Phe) in exon 9 of the gene has been described.…”