2. Academic Validation
  3. EPT1 (selenoprotein I) is critical for the neural development and maintenance of plasmalogen in humans

EPT1 (selenoprotein I) is critical for the neural development and maintenance of plasmalogen in humans

  • J Lipid Res. 2018 Jun;59(6):1015-1026. doi: 10.1194/jlr.P081620.
Yasuhiro Horibata 1,  Orly Elpeleg 2,  Ayelet Eran 3,  Yoshio Hirabayashi 4,  David Savitzki 5,  Galit Tal 6,  Hanna Mandel 7,  Hiroyuki Sugimoto 8
Affiliations

Affiliations

  • 1 Department of Biochemistry, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan.
  • 2 Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
  • 3 Department of Diagnostic Imaging, Rambam Health Care Campus, Haifa, Israel.
  • 4 Molecular Membrane Neuroscience, RIKEN Brain Science Institute, Wako, Saitama, Japan.
  • 5 Pediatric Neurology Unit, Galilee Medical Center, Nahariya, Israel.
  • 6 Metabolic Unit, Rambam Health Care Campus, Rappaport School of Medicine, Haifa, Israel.
  • 7 Metabolic Unit, Rambam Health Care Campus, Rappaport School of Medicine, Haifa, Israel. Electronic address: [email protected].
  • 8 Department of Biochemistry, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan. Electronic address: [email protected].
PMID: 29500230 DOI: 10.1194/jlr.P081620
Abstract

Ethanolamine phosphotransferase (EPT)1, also known as selenoprotein 1 (SELENOI), is an Enzyme that transfers phosphoethanolamine from cytidine diphosphate-ethanolamine to lipid acceptors to produce ethanolamine glycerophospholipids, such as diacyl-linked phosphatidylethanolamine (PE) and ether-linked plasmalogen [1-alkenyl-2-acyl-glycerophosphoethanolamine (plasmenyl-PE)]. However, to date there has been no analysis of the metabolomic consequences of the mutation of EPT1 on the concentration of ethanolamine glycerophospholipids in mammalian cells. We studied a patient with severe complicated hereditary spastic paraplegia, sensorineural-deafness, blindness, and seizures. Neuroimaging revealed hypomyelination, followed by brain atrophy mainly in the cerebellum and brainstem. Using whole exome sequencing, we identified a novel EPT1 mutation (exon skipping). In vitro EPT activity, as well as the rate of biosynthesis of ethanolamine glycerophospholipids, was markedly reduced in cultures of the patient's skin fibroblasts. Quantification of Phospholipids by LC-MS/MS demonstrated reduced levels of several PE species with polyunsaturated fatty acids, such as 38:6, 38:4, 40:6, 40:5, and 40:4. Notably, most plasmenyl-PE species were significantly decreased in the patient's cells, whereas most plasmanylcholine [1-alkyl-2-acyl-glycerophosphocholine (plasmanyl-PC)] species were increased. Similar findings regarding decreased plasmenyl-PE and increased plasmanyl-PC were obtained using EPT1-KO HeLa cells. Our data demonstrate for the first time the indispensable role of EPT1 in the myelination process and neurodevelopment, and in the maintenance of normal homeostasis of ether-linked Phospholipids in humans.

Keywords

ethanolamine phosphotransferase 1; hereditary spastic paraplegia; neurodegenerative disease; phospholipids/biosynthesis; phospholipids/metabolism; phospholipids/phosphatidylcholine; phospholipids/phosphatidylethanolamine; whole exome sequencing.

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