演題詳細

一般口演 / Oral Session

一般口演 32 (Oral Session 32) :巨核球造血・血小板減少症

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日程
2013年10月11日(金)
時間
15:25 - 16:25
会場
第13会場 / Room No.13 (札幌市教育文化会館 3F 研修室301)
座長・司会
冨山 佳昭 (Yoshiaki Tomiyama):1
1:大阪大学医学部附属病院 輸血部
 
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ACTN1 mutations cause congenital macrothrombocytopenia

演題番号 : OS-1-163

國島 伸治 (Shinji Kunishima):1、奥野 友介 (Yusuke Okuno):2、吉田 健一 (Kenichi Yoshida):2、白石 友一 (Yuichi Shiraishi):3、真田 昌 (Masashi Sanada):2、村松 秀城 (Hideki Muramatsu):4、千葉 健一 (Kenichi Chiba):3、田中 洋子 (Hiroko Tanaka):3、宮崎 浩二 (Koji Miyazaki):5、酒井 道生 (Michio Sakai):6、大竹 正俊 (Masatoshi Ohtake):7、小林 良二 (Ryoji Kobayashi):8、井口 晶裕 (Akihiro Iguchi):9、新美 元 (Gen Niimi):10、大津 真 (Makoto Otsu):3、高橋 義行 (Yoshiyuki Takahashi):4、宮野 悟 (Satoru Miyano):3、齋藤 英彦 (Hidehiko Saito):1、小島 勢二 (Seiji Kojima):4、小川 誠司 (Seishi Ogawa):2

1:Clinical Research Center, Nagoya Medical Center, Nagoya, Japan、2:Cancer Genomics Project, Tokyo University, Tokyo, Japan、3:Institute of Medical Science, Tokyo University, Tokyo, Japan、4:Department of Pediatrics, Nagoya University, Nagoya, Japan、5:Department of Hematology, Kitasato University, Kanagawa, Japan、6:Department of Pediatrics, University of Occupational and Environmental Health, Kitakyushu, Japan、7:Division of Pediatrics, Sendai City Hospital, Miyagi, Japan、8:Department of Pediatrics, Sapporo Hokuyu Hospital, Sapporo, Japan、9:Department of Pediatrics, Hokkaido University, Sapporo, Japan、10:Laboratory of Electron Microscopy, Fujita Health University, Toyoake, Japan

 

Congenital macrothrombocytopenia (CMTP) is a heterogeneous group of rare platelet disorders, characterized by a congenital reduction of platelet counts and abnormally large platelets, for which CMTP-causing mutations are only found in approximately half the cases. We herein performed whole exome sequencing and targeted Sanger sequencing to identify mutations that cause CMTP, in which a dominant mode of transmission had been suspected but no known responsible mutations had been documented. In 13 Japanese CMTP pedigrees, we identified six pedigrees (46%) with ACTN1 variants, which co-segregated with CMTP. In the entire cohort, ACNT1 variants accounted for 5.5% of the dominant forms of CMTP cases and represent the fourth most common cause in Japanese individuals. Individuals with variant ACTN1 presented moderate macrothrombocytopenia with anisocytosis, but were either asymptomatic or associated with only a modest bleeding tendency. ACTN1 encodes &alpha-actinin-1, a member of the actin-crosslinking protein superfamily that participates in the organization of the cytoskeleton. In vitro transfection experiments in Chinese hamster ovary cells demonstrated that mutant &alpha-actinin-1 disrupted the normal actin-based cytoskeletal structure. Moreover, transduction of mouse fetal liver-derived megakaryocytes with disease-associated ACTN1-variants caused a disorganized actin-based cytoskeleton in megakaryocytes, resulting in the production of abnormally large proplatelet tips, which were reduced in number. Our findings provide an insight into the pathogenesis of CMTP.

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