ALOX12 mutation in a family with dominantly inherited bleeding diathesis

Tetsuo Mitsui, Satoshi Makino, Gen Tamiya, Hiroko Sato, Yuki Kawakami, Yoshitaka Takahashi, Toru Meguro, Hiroko Izumino, Yosuke Sudo, Ikuo Norota, Kuniaki Ishii, Kiyoshi Hayasaka

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)753-759
Number of pages7
JournalJournal of Human Genetics
Issue number8
Publication statusPublished - 2021 Aug

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


Dive into the research topics of 'ALOX12 mutation in a family with dominantly inherited bleeding diathesis'. Together they form a unique fingerprint.

Cite this