ALOX12 mutation in a family with dominantly inherited bleeding diathesis

J Hum Genet. 2021 Aug;66(8):753-759. doi: 10.1038/s10038-020-00887-6. Epub 2021 Feb 10.


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 A2 (TXA2) 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, TXA2 mimetic U46619, collagen, and AA, normal affinity of TXA2 receptor for U46619, and normal induction of GTPase activity upon stimulation with U46619. However, the production of inositol 1,4,5-triphosphate (IP3) was only increased up to 30% of the control upon U46619 stimulation, suggesting a defect in phospholipase C-β2 (PLCB2) activation downstream from TXA2 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.

MeSH terms

  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / metabolism
  • Arachidonate 12-Lipoxygenase / genetics*
  • Arachidonic Acid / metabolism
  • Blood Coagulation Disorders, Inherited / genetics*
  • Blood Platelets / physiology*
  • Calcium / metabolism
  • Disease Susceptibility
  • GTP Phosphohydrolases / metabolism
  • Genetic Predisposition to Disease*
  • Hemorrhage / genetics*
  • Hemorrhage / metabolism
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Inositol 1,4,5-Trisphosphate / metabolism
  • Mutation
  • Pedigree
  • Phospholipase C beta / metabolism
  • Platelet Aggregation
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • Signal Transduction
  • Thromboxane A2 / metabolism


  • Arachidonic Acid
  • Thromboxane A2
  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
  • Inositol 1,4,5-Trisphosphate
  • Arachidonate 12-Lipoxygenase
  • ALOX12 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • PLCB2 protein, human
  • Phospholipase C beta
  • GTP Phosphohydrolases
  • Calcium