ALOX12 mutation in a family with dominantly inherited bleeding diathesis
JOURNAL OF HUMAN GENETICS(2021)
Abstract
The arachidonic acid (AA) cascade plays a significant role in platelet aggregation. AA released from membrane phospholipids is metabolized by cyclooxygenase (COX) pathway to thromboxane A 2 (TXA 2 ) or by 12S-lipoxygenase (ALOX12) to 12-hydroperoxyeicosatetraenoic acid (12-HPETE). In contrast to a well-known role of the COX pathway in platelet aggregation, the role of ALOX12 is not well understood. Platelets of ALOX12-deficient mice exhibit increased sensitivity for ADP-induced aggregation. However, recent evidence strongly suggests a significant role of ALOX12 in platelet aggregation and calcium signaling. 12-HPETE potentiates thrombin- and thromboxane-induced platelet aggregation, and calcium signaling. Inhibition experiments of ALOX12 demonstrated decreased platelet aggregation and calcium signaling in stimulated platelets. We studied a family with a dominantly inherited bleeding diathesis using next-generation sequencing analysis. Platelet aggregation studies revealed that the proband’s platelets had defective aggregation responses to ADP, TXA 2 mimetic U46619, collagen, and AA, normal affinity of TXA 2 receptor for U46619, and normal induction of GTPase activity upon stimulation with U46619. However, the production of inositol 1,4,5-triphosphate (IP 3 ) was only increased up to 30% of the control upon U46619 stimulation, suggesting a defect in phospholipase C-β2 (PLCB2) activation downstream from TXA 2 receptors. Affected family members had no mutation of PLCB2 , but had a heterozygous c.1946A > G (p.Tyr649Cys) mutation of ALOX12 . ALOX12 activity in platelets from the affected members was decreased to 25–35% of the control. Our data strongly suggested that a heterozygous c.1946A > G ALOX12 mutation was a disease-causing mutation; however, further experiments are required to confirm the pathogenesis of ALOX12 mutation in platelet aggregation.
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Key words
Disease genetics,Haematological diseases,Human Genetics,Molecular Medicine,Gene Function,Gene Expression,Gene Therapy
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