{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T12:58:54Z","timestamp":1782824334253,"version":"3.54.5"},"reference-count":53,"publisher":"American Society of Hematology","issue":"20","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,10,26]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Sphingomyelin synthase 1 (SMS1) contributes to the generation of membrane sphingomyelin (SM) and affects SM-mediated physiological functions. Here, we describe the hematologic phenotypes, such as reduced circulating platelets and dysfunctional hemostasis, in SMS1-deficient (SMS1-KO) mice. SMS1-KO mice display pathologic manifestations related to idiopathic thrombocytopenia (ITP), including relatively high amounts of peripheral blood reticulated platelets, enhanced megakaryopoiesis in the bone marrow and spleen, and splenomegaly. Deficiency of SMS1, but not SMS2, prevented SM production and enhanced phosphatidylserine (PS) externalization on the plasma membranes of platelets and megakaryocytes. Consequently, SMS1-KO platelets were excessively cleared by macrophages in the spleen. Multimer formation in the plasma membrane of TMEM16F, a known calcium (Ca2+)-activated nonselective ion channel and Ca2+-dependent PS scramblase, was enhanced; the result was PS externalization to outer leaflets through increased Ca2+ influx in immortalized mouse embryonic fibroblasts established from SMS1-KO mice (SMS1-KO tMEFs), as seen with SMS1-KO platelets. Thus, SMS1 deficiency changed the TMEM16F distribution on the membrane microdomain, regulating Ca2+ influx-dependent PS exposure. SMS1-KO tMEFs in which TMEM16F was knocked out by using the CRISPR\/Cas9 system lacked both the Ca2+ influx and excess PS exposure seen in SMS1-KO tMEFs. Therefore, SM depletion on platelet membrane microdomains due to SMS1 deficiency enhanced PS externalization via a Ca2+ influx through TMEM16F activation, leading to elevated platelet clearance and causing hemostasis dysfunction through thrombocytopenia. Our current findings show that the SM-rich microdomain generated by SMS1 is a potent regulator of thrombocytopenia through TMEM16F, suggesting that its dysfunction may be a novel additional mechanism of ITP.<\/jats:p>","DOI":"10.1182\/bloodadvances.2020002922","type":"journal-article","created":{"date-parts":[[2021,10,26]],"date-time":"2021-10-26T16:29:33Z","timestamp":1635265773000},"page":"4265-4277","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":12,"title":["A novel mechanism of thrombocytopenia by PS exposure through TMEM16F in sphingomyelin synthase 1 deficiency"],"prefix":"10.1182","volume":"5","author":[{"given":"Yoritaka","family":"Fujii","sequence":"first","affiliation":[{"name":"Department of General and Digestive Surgery, Faculty of 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Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5937-3915","authenticated-orcid":false,"given":"Chieko","family":"Hashizume","sequence":"additional","affiliation":[{"name":"Department of General and Digestive Surgery, Faculty of Medicine,"},{"name":"Department of Hematology and Immunology, Faculty of Medicine, Kanazawa Medical University, Kahoku, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Bone and Joint Disease, National Center for Geriatrics and Gerontology, Aichi, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Takeya","sequence":"additional","affiliation":[{"name":"Department of Applied Life Science, Sojo University, Kumamoto, Japan; 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