title: Lenz-Majewski mutations in PTDSS1 affect phosphatidylinositol 4-phosphate metabolism at ER-PM and ER-Golgi junctions.
abstract: Lenz-Majewski syndrome (LMS) is a rare disease characterized by complex craniofacial, dental, cutaneous, and limb abnormalities combined with intellectual disability. Mutations in thePTDSS1gene coding one of the phosphatidylserine (PS) synthase enzymes, PSS1, were described as causative in LMS patients. Such mutations render PSS1 insensitive to feedback inhibition by PS levels. Here we show that expression of mutant PSS1 enzymes decreased phosphatidylinositol 4-phosphate (PI4P) levels both in the Golgi and the plasma membrane (PM) by activating the Sac1 phosphatase and altered PI4P cycling at the PM. Conversely, inhibitors of PI4KA, the enzyme that makes PI4P in the PM, blocked PS synthesis and reduced PS levels by 50% in normal cells. However, mutant PSS1 enzymes alleviated the PI4P dependence of PS synthesis. Oxysterol-binding protein-related protein 8, which was recently identified as a PI4P-PS exchanger between the ER and PM, showed PI4P-dependent membrane association that was significantly decreased by expression of PSS1 mutant enzymes. Our studies reveal that PS synthesis is tightly coupled to PI4P-dependent PS transport from the ER. Consequently, PSS1 mutations not only affect cellular PS levels and distribution but also lead to a more complex imbalance in lipid homeostasis by disturbing PI4P metabolism.
authors.affiliation: Section on Molecular Signal Transduction, Program for Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Mira
authors.initials: M
authors.lastname: Sohn
authors.affiliation: Department of Pharmacology and Biochemistry, Vanderbilt-Ingram Cancer Center, The Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232;
authors.forename: Pavlina
authors.initials: P
authors.lastname: Ivanova
authors.affiliation: Department of Pharmacology and Biochemistry, Vanderbilt-Ingram Cancer Center, The Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232;
authors.forename: H Alex
authors.initials: HA
authors.lastname: Brown
authors.affiliation: Section on Molecular Signal Transduction, Program for Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Daniel J
authors.identifier: http://orcid.org/0000-0001-6670-3348
authors.initials: DJ
authors.lastname: Toth
authors.affiliation: Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary, H-1094.
authors.forename: Peter
authors.initials: P
authors.lastname: Varnai
authors.affiliation: Section on Molecular Signal Transduction, Program for Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Yeun Ju
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Section on Molecular Signal Transduction, Program for Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; ballat@mail.nih.gov.
authors.forename: Tamas
authors.initials: T
authors.lastname: Balla
mesh_terms: D000015:Abnormalities, Multiple / Q000201:enzymology* / Q000235:genetics; D001848:Bone Diseases, Developmental / Q000201:enzymology* / Q000235:genetics; D002462:Cell Membrane / Q000201:enzymology* / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000201:enzymology* / Q000235:genetics; D006056:Golgi Apparatus / Q000201:enzymology* / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008607:Intellectual Disability / Q000201:enzymology* / Q000235:genetics; D015778:Minor Histocompatibility Antigens; D009154:Mutation; D019884:Nitrogenous Group Transferases / Q000235:genetics / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000235:genetics / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism
chemical_list: D015778:Minor Histocompatibility Antigens; D018129:Phosphatidylinositol Phosphates; C037178:phosphatidylinositol 4-phosphate; D019884:Nitrogenous Group Transferases; D017853:Phosphotransferases (Alcohol Group Acceptor); C402182:phosphatidylinositol phosphate 4-kinase; C022370:phospholipid serine base exchange enzyme
keywords: ER-PM junctions; PI 4-kinase; lipid transfer; phosphatidylinositol; phosphatidylserine