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ALOX12 mutation in a family with dominantly inherited bleeding diathesis

Journal of Human Genetics volume 66, pages 753–759 (2021)Cite this article

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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 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.

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Acknowledgements

We express our gratitude to the family for participating in this study. We would also like to thank Ms. Yumiko Kishikawa for her technical assistance.

Funding

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan

    Tetsuo Mitsui, Hiroko Sato, Toru Meguro, Hiroko Izumino, Yosuke Sudo & Kiyoshi Hayasaka

  2. Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan

    Satoshi Makino & Gen Tamiya

  3. Statistical Genetics Team, RIKEN Center for Advanced Intelligence Project, Tokyo, Japan

    Gen Tamiya

  4. Department of Nutritional Science, Faculty of Health and Welfare Science, Okayama Prefectural University, Okayama, Japan

    Yuki Kawakami & Yoshitaka Takahashi

  5. Department of Pharmacology, Yamagata University School of Medicine, Yamagata, Japan

    Ikuo Norota & Kuniaki Ishii

  6. Department of Pediatrics, Miyukikai Hospital, Social Medical Corporation Miyuki, Kaminoyama, Japan

    Kiyoshi Hayasaka

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  1. Tetsuo Mitsui
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Correspondence to Tetsuo Mitsui, Gen Tamiya or Kiyoshi Hayasaka.

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The authors declare that they have no conflict of interest.

Ethics

The ethics committee of the Yamagata University School of Medicine approved our research project (reference number 397/2015). All procedures followed were in accordance with the Helsinki Declaration of 1975, as revised in 2000. The informed consent for the molecular analysis was obtained from the members of the family.

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Mitsui, T., Makino, S., Tamiya, G. et al. ALOX12 mutation in a family with dominantly inherited bleeding diathesis. J Hum Genet 66, 753–759 (2021). https://doi.org/10.1038/s10038-020-00887-6

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  • DOI: https://doi.org/10.1038/s10038-020-00887-6

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