Inherited human cPLA2α deficiency is associated with impaired eicosanoid biosynthesis, small intestinal ulceration, and platelet dysfunction

Abstract

Cytosolic phospholipase A 2α (cPLA 2α ) hydrolyzes arachidonic acid from cellular membrane phospholipids, thereby providing enzymatic substrates for the synthesis of eicosanoids, such as prostaglandins and leukotrienes. Considerable understanding of cPLA 2α function has been derived from investigations of the enzyme and from cPLA 2α -null mice, but knowledge of discrete roles for this enzyme in humans is limited. We investigated a patient hypothesized to have an inherited prostanoid biosynthesis deficiency due to his multiple, complicated small intestinal ulcers despite no use of cyclooxygenase inhibitors. Levels of thromboxane B 2 and 12-hydroxyeicosatetraenoic acid produced by platelets and leukotriene B 4 released from calcium ionophore-activated blood were markedly reduced, indicating defective enzymatic release of the arachidonic acid substrate for the corresponding cyclooxygenase and lipoxygenases. Platelet aggregation and degranulation induced by adenosine diphosphate or collagen were diminished but were normal in response to arachidonic acid. Two heterozygous single base pair mutations and a known SNP were found in the coding regions of the patient's cPLA 2α genes (p.[Ser111Pro]+[Arg485His; Lys651Arg]). The total PLA 2 activity in sonicated platelets was diminished, and the urinary metabolites of prostacyclin, prostaglandin E 2 , prostaglandin D 2 , and thromboxane A 2 were also reduced. These findings characterize what we believe is a novel inherited deficiency of cPLA 2 .

Cytosolic phospholipase A2: physiological function and role in disease

“…In one subject, two rare heterozygous single bp mutations in PLA2G4A were found; one mutation (S111P) occurred in the C2 domain of cPLA 2 ␣ and the other allele had a mutation in the catalytic domain (R485H) ( Fig. 2 ) ( 49 ). The expression of cPLA 2 ␣ protein and PLA 2 activity in platelet lysates was reduced compared with normals.…”

“…The consequences of inherited cPLA 2 ␣ defi ciency in several human patients have now been described (49)(50)(51). against colon cancer in mice induced by the colon carcinogen, azoxymethane, which induces increased tumor multiplicity in heterozygous and KO mice compared with WT mice ( 131 ).…”

“…The generation of mice defi cient in cPLA 2 ␣ has revealed its role in regulating normal physiological processes and disease pathogenesis in rodents ( 47,48 ). More recently, the identifi cation of humans with cPLA 2 ␣ defi ciency has emphasized its important role in human health (49)(50)(51). This review will provide a brief overview of the regulation of cPLA 2 ␣ and primarily focus on reviewing its function in specifi c organs of mice and humans.…”

Phospholipase A2 structure/function, mechanism, and signaling

“…Both of these inhibitors have been used for in vivo animal models of inflammation and have shown potency in reducing inflammatory effects (40,41). Potential side effects of GIVA PLA 2 inhibitors have been suggested by recent work examining a human patient with defects in GIVA PLA 2 who showed decreases in PLA 2 activity, eicosanoid biosynthesis, and the generation of many small intestinal ulcers (42).…”

Thematic Review Series: Proteomics. An integrated omics analysis of eicosanoid biology

“…Bonventre et al (18) and Uozumi et al (19) independently demonstrated that peritoneal macrophages from Group IVA PLA 2 knockout mice were incapable of producing eicosanoids. More recently, Adler et al (20) identified a patient with inherited Group IVA deficiency and determined that nearly all arachidonic acid used for eicosanoid production by platelets and circulating leukocytes was attributable to this enzyme. The Group IVA cPLA 2 uses a catalytic Ser/Asp dyad to hydrolyze fatty acids and contains a C2 domain that facilitates calcium-dependent translocation from the cytosol to the membrane surface where it encounters phospholipid substrate.…”