カンノ　ヒトシ   菅野　仁    所属   医学部 医学科（東京女子医科大学病院）    職種   特任教授
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	ATP11C is a major flippase in human erythrocytes and its defect causes congenital hemolytic anemia.
掲載誌名	正式名：Haematologica 略　 称：Haematologica ISSNコード：(15928721)0390-6078
掲載区分	国外
巻・号・頁	101(5),pp.559-565
著者・共著者	Arashiki Nobuto, Takakuwa Yuichi, Mohandas Narla, Hale John, Yoshida Kenichi, Ogura Hiromi, Utsugisawa Taiju, Ohga Shouichi, Miyano Satoru, Ogawa Seishi, Kojima Seiji, Kanno Hitoshi
担当区分	最終著者,責任著者
発行年月	2016/05
概要	Phosphatidylserine is localized exclusively to the inner leaflet of the membrane lipid bilayer of most cells, including erythrocytes. This asymmetric distribution is critical for the survival of erythrocytes in circulation since externalized phosphatidylserine is a phagocytic signal for splenic macrophages. Flippases are P-IV ATPase family proteins that actively transport phosphatidylserine from the outer to inner leaflet. It has not yet been determined which of the 14 members of this family of proteins is the flippase in human erythrocytes. Herein, we report that ATP11C encodes a major flippase in human erythrocytes, and a genetic mutation identified in a male patient caused congenital hemolytic anemia inherited as an X-linked recessive trait. Phosphatidylserine internalization in erythrocytes with the mutant ATP11C was decreased 10-fold compared to that of the control, functionally establishing that ATP11C is a major flippase in human erythrocytes. Contrary to our expectations phosphatidylserine was retained in the inner leaflet of the majority of mature erythrocytes from both controls and the patient, suggesting that phosphatidylserine cannot be externalized as long as scramblase is inactive. Phosphatidylserine-exposing cells were found only in the densest senescent cells (0.1% of total) in which scramblase was activated by increased Ca(2+) concentration: the percentage of these phosphatidylserine-exposing cells was increased in the patient's senescent cells accounting for his mild anemia. Furthermore, the finding of similar extents of phosphatidylserine exposure by exogenous Ca(2+)-activated scrambling in both control erythrocytes and the patient's erythrocytes implies that suppressed scramblase activity rather than flippase activity contributes to the maintenance of phosphatidylserine in the inner leaflet of human erythrocytes.
DOI	10.3324/haematol.2016.142273
PMID	26944472