Background Cytosolic phospholipase A2-a (cPLA2-a) has been implicated in many human pathophysiologic processes because it regulates cyclooxygenase (COX)- and lipoxygenase (LOX)-mediated eicosanoid production by catalyzing the release of their substrate, arachidonic acid (AA), from membrane phospholipids. Although mouse gene-deletion models have explored the phenotype of cPLA2-a deficiency in that species, no human deficiency of this enzyme has been previously reported. We report and characterize an inherited cPLA2-a deficiency in a 45-year-old male with chronic gastrointestinal blood loss and recurrent small intestinal ulcers.
Methods/Results The patient's mean platelet PLA2 activity was 0.77 6 0.32 pmol/min/50 μg protein vs 2.83 6 0.47 pmol/min/50 μg protein for controls (p < .0005). Western blot analysis of platelet protein compared with controls demonstrated decreased cPLA2-a with expected molecular weight. Sequencing of cPLA2-a cDNA demonstrated 3 heterozygous nonsynonymous single base pair mutations: Ser111Pro (S111P), Arg485His (R485H), and Lys651Arg (K651R). The patient's mother possessed the heterozygous S111P mutation and sister possessed both the heterozygous R485H and K651R mutations. COX- and LOX-mediated AA metabolites were quantified in urine and blood from the patient by mass spectrometry. Prostaglandin metabolites in urine were significantly reduced. Serum thromboxane B2 (TxB2) production was 4.6% of normal controls (p < .006) and serum 12-HETE was 1.3% of controls (p < .005). Optical platelet aggregation in response to ADP and collagen was blunted but was normal in response to AA. Luminescence monitoring of ATP release by platelets demonstrated diminished granule secretion in response to collagen and absent response to ADP. Ex vivo AA-triggered endogenous AA release was remarkably depressed in washed platelets, but TxB2 production from exogenous deuterated AA was normal.
Conclusion We describe a novel compound heterozygous mutation of cPLA2-a resulting in decreased eicosanoid production, multiple recurrent small intestinal ulcers, altered platelet function, and chronic gastrointestinal blood loss in an adult male. These findings provide perspective for considerations of the development of drugs that target cPLA2-a and further characterization of this deficiency has the potential for elucidating the biology and pathophysiologic role of cPLA2-a.
Supported by NIH grants GM-15431, U01 HL65962, and M01 RR-00095.
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