ArticleThe Journal of clinical investigation2021
A sublethal ATP11A mutation associated with neurological deterioration causes aberrant phosphatidylcholine flipping in plasma membranes.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 46 citations in OpenAlex.
- Early oligodendrocyte dysfunction signature in Alzheimer's disease: Insights from DNA methylomics and transcriptomics.Molecular psychiatry · 2026Article
- Glycerophospholipids: Roles in Cell Trafficking and Associated Inborn Errors.Journal of inherited metabolic disease · 2025Review
- Substrates, regulation, cellular functions, and disease associations of P4-ATPases.Communications biology · 2025Review
- TMEM63B scrambles phospholipids in response to changes in membrane structure.Nature structural & molecular biology · 2025Article
- Membrane structure-responsive lipid scrambling by TMEM63B to control plasma membrane lipid distribution.Nature structural & molecular biology · 2025Article
- The danger of flipping an outside lipid to the inside.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Substrate specificity controlled by the exit site of human P4-ATPases, revealed by de novo point mutations in neurological disorders.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- P4-ATPase endosomal recycling relies on multiple retromer-dependent localization signals.Molecular biology of the cell · 2024Article
- Role of Enzymes Capable of Transporting Phosphatidylserine in Brain Development and Brain Diseases.ACS omega · 2024Review
- DNA methylation patterns in umbilical cord blood from infants of methadone maintained opioid dependent mothers.Scientific reports · 2024Article
- Functional and in silico analysis of ATP8A2 and other P4-ATPase variants associated with human genetic diseases.Disease models & mechanisms · 2024Article
- Flipping the script: Advances in understanding how and why P4-ATPases flip lipid across membranes.Biochimica et biophysica acta. Molecular cell research · 2024Review
- Inhibition of miR-4763-3p expression activates the PI3K/mTOR/Bcl2 autophagy signaling pathway to ameliorate cognitive decline.International journal of biological sciences · 2024Article
- GWAS-significant loci and severe COVID-19: analysis of associations, link with thromboinflammation syndrome, gene-gene, and gene-environmental interactions.Frontiers in genetics · 2024Article
- Article
- ATP11A Promotes Epithelial-mesenchymal Transition in Gastric Cancer Cells via the Hippo Pathway.Journal of Cancer · 2024Article
- Intestinal Atp8b1 dysfunction causes hepatic choline deficiency and steatohepatitis.Nature communications · 2023Article
- Alternative splicing in lung influences COVID-19 severity and respiratory diseases.Nature communications · 2023Article
- Molecular Pathogenic Mechanisms of Hypomyelinating Leukodystrophies (HLDs).Neurology international · 2023Review
- Regulation of phospholipid distribution in the lipid bilayer by flippases and scramblases.Nature reviews. Molecular cell biology · 2023Review
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Authors and funding
23 authors at 9 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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