2. Academic Validation
  3. A sublethal ATP11A mutation associated with neurological deterioration causes aberrant phosphatidylcholine flipping in plasma membranes

A sublethal ATP11A mutation associated with neurological deterioration causes aberrant phosphatidylcholine flipping in plasma membranes

  • J Clin Invest. 2021 Sep 15;131(18):e148005. doi: 10.1172/JCI148005.
Katsumori Segawa 1,  Atsuo Kikuchi 2,  Tomoyasu Noji 3,  Yuki Sugiura 4,  Keita Hiraga 3,  Chigure Suzuki 5 6,  Kazuhiro Haginoya 7 8,  Yasuko Kobayashi 7 9,  Mitsuhiro Matsunaga 1,  Yuki Ochiai 1,  Kyoko Yamada 1,  Takuo Nishimura 1,  Shinya Iwasawa 2,  Wataru Shoji 10,  Fuminori Sugihara 11,  Kohei Nishino 12,  Hidetaka Kosako 12,  Masahito Ikawa 13,  Yasuo Uchiyama 5 6,  Makoto Suematsu 4,  Hiroshi Ishikita 3,  Shigeo Kure 2 14,  Shigekazu Nagata 1 15
Affiliations

Affiliations

  • 1 Laboratory of Biochemistry and Immunology, World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
  • 2 Department of Pediatrics, Tohoku University School of Medicine, Sendai, Miyagi, Japan.
  • 3 Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
  • 4 Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan.
  • 5 Department of Cellular and Molecular Pharmacology and.
  • 6 Department of Cellular and Neuropathology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
  • 7 Department of Pediatric Neurology, Takuto Rehabilitation Center for Children, Sendai, Miyagi, Japan.
  • 8 Department of Pediatric Neurology, Miyagi Children's Hospital, Sendai, Miyagi, Japan.
  • 9 Department of Pediatrics, National Hospital Organization Sendai-Nishitaga Hospital, Sendai, Miyagi, Japan.
  • 10 Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai, Miyagi, Japan.
  • 11 Central Instrumentation Laboratory, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
  • 12 Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, Tokushima University, Tokushima, Japan.
  • 13 Department of Experimental Genome Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
  • 14 Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan.
  • 15 Center for Infectious Disease Education and Research, Osaka University, Suita, Osaka, Japan.
PMID: 34403372 DOI: 10.1172/JCI148005
Abstract

ATP11A translocates phosphatidylserine (PtdSer), but not phosphatidylcholine (PtdCho), from the outer to the inner leaflet of plasma membranes, thereby maintaining the asymmetric distribution of PtdSer. Here, we detected a de novo heterozygous point mutation of ATP11A in a patient with developmental delays and neurological deterioration. Mice carrying the corresponding mutation died perinatally of neurological disorders. This mutation caused an amino acid substitution (Q84E) in the first transmembrane segment of ATP11A, and mutant ATP11A flipped PtdCho. Molecular dynamics simulations revealed that the mutation allowed PtdCho binding at the substrate entry site. Aberrant PtdCho flipping markedly decreased the concentration of PtdCho in the outer leaflet of plasma membranes, whereas sphingomyelin (SM) concentrations in the outer leaflet increased. This change in the distribution of Phospholipids altered cell characteristics, including cell growth, Cholesterol homeostasis, and sensitivity to sphingomyelinase. Matrix-assisted laser desorption ionization-imaging mass spectrometry (MALDI-IMS) showed a marked increase of SM levels in the brains of Q84E-knockin mouse embryos. These results provide insights into the physiological importance of the substrate specificity of plasma membrane flippases for the proper distribution of PtdCho and SM.

Keywords

Cell Biology; Cholesterol; Metabolism; Mouse models.

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