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

• Published in: The Journal of clinical investigation Vol. 131; no. 18; pp. 1 - 17
• Main Authors: Segawa, Katsumori, Kikuchi, Atsuo, Noji, Tomoyasu, Sugiura, Yuki, Hiraga, Keita, Suzuki, Chigure, Haginoya, Kazuhiro, Kobayashi, Yasuko, Matsunaga, Mitsuhiro, Ochiai, Yuki, Yamada, Kyoko, Nishimura, Takuo, Iwasawa, Shinya, Shoji, Wataru, Sugihara, Fuminori, Nishino, Kohei, Kosako, Hidetaka, Ikawa, Masahito, Uchiyama, Yasuo, Suematsu, Makoto, Ishikita, Hiroshi, Kure, Shigeo, Nagata, Shigekazu
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 15.09.2021
• Subjects: Adenosine triphosphatase; Adult; Amino Acid Sequence; Amino Acid Substitution; Animals; ATP Binding Cassette Transporter 1 - deficiency; ATP Binding Cassette Transporter 1 - genetics; ATP Binding Cassette Transporter 1 - metabolism; ATP-Binding Cassette Transporters - chemistry; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Biomedical research; Brain; Brain - diagnostic imaging; Cell Membrane - metabolism; Cell membranes; Child development deviations; Cholesterol; Development and progression; Developmental disabilities; Embryos; Eye movements; Female; Fibroblasts; Gene mutations; Genes, Lethal; Genetic aspects; Glycerophospholipids; Health aspects; Heterozygote; Homeostasis; Humans; Lecithin; Lipids; Male; Mass spectrometry; Mass spectroscopy; Membrane Lipids - metabolism; Membranes; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Mutant Strains; Molecular Dynamics Simulation; Mutation; Nervous system diseases; Neurodegenerative Diseases - diagnostic imaging; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - metabolism; Neurological diseases; Neurological disorders; Neurological research; Peptides; Phosphatidylcholine; Phosphatidylcholines - metabolism; Phosphatidylserine; Phospholipid Transfer Proteins - genetics; Phospholipid Transfer Proteins - metabolism; Phospholipids; Placenta; Plasma; Plasma membranes; Point Mutation; Pregnancy; Proteins; Rodents; Scientific imaging; Sperm; Sphingomyelin; Sphingomyelin phosphodiesterase; Substrate specificity; Japan; Metabolism; Mouse models; Cholesterol; Cell Biology
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI148005

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.