Elucidation of the relationship between phospholipid flippase ATP8B2 mutation and intellectual disabilities

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07325
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: Kyoto University
• Principal Investigator: TAKATSU Hiroyuki 京都大学, 薬学研究科, 研究員 (70360576)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: ATP8B2 / 知的障害 / フリッパーゼ / ATP8B1 / ATP11C

Outline of Final Research Achievements

P4-ATPases are lipid flippases that translocate lipids from the exoplasmic (or luminal) to the cytoplasmic leaflet of biological membranes. ATP8B2 is found to be a phosphatidylcholine(PC)-flippase at the plasma membrane but its physiological function is unknown. This time, I found three de novo heterozygous point mutations of ATP8B2 gene in intellectual disabilities patients. The three de novo mutations did not affect the interaction with CDC50A and localization to the plasma membrane. However, two mutations dramatically reduced the phosphatidylcholine flippase activity of ATP8B2. Notably, these amino acids were conserved in all members of the P4-ATPase family. The corresponding mutations in ATP8B1 and ATP11C also decreased PC- and phosphatidylserine-flippase activity, respectively, suggesting that these amino acids are functionally conserved and important in the enzymatic activity of P4-ATPase family.

Free Research Field

分子細胞生物学

Academic Significance and Societal Importance of the Research Achievements

知的障害患者の網羅的遺伝子解析から明らかになったATP8B2の変異は、遺伝性の知的障害の原因遺伝子の一つとして新たにATP8B2をクローズアップした。医学的見地からも、細胞生物学的立場からも、全く新しい展開であり、ATP8B2の膜脂質の動態制御と知的障害発症の相関を世界で初めて明らかにするものである。また、本研究により、ATP8B2で見出された変異が、P4-ATPase全般のフリッパーゼ活性に共通の重要な残基を新たに明らかにした。このことは、分子生物学のみならず、構造生物学的にもとても興味深い点であり、今後のフリッパーゼの研究において重要な知見を与えるものと考えている。