title: PNPLA1 Deficiency in Mice and Humans Leads to a Defect in the Synthesis of Omega-O-Acylceramides.
abstract: Mutations in PNPLA1 have been identified as causative for autosomal recessive congenital ichthyosis in humans and dogs. So far, the underlying molecular mechanisms are unknown. In this study, we generated and characterized PNPLA1-deficient mice and found that PNPLA1 is crucial for epidermal sphingolipid synthesis. The absence of functional PNPLA1 in mice impaired the formation of omega-O-acylceramides and led to an accumulation of nonesterified omega-hydroxy-ceramides. As a consequence, PNPLA1-deficient mice lacked a functional corneocyte-bound lipid envelope leading to a severe skin barrier defect and premature death of newborn animals. Functional analyses of differentiated keratinocytes from a patient with mutated PNPLA1 demonstrated an identical defect in omega-O-acylceramide synthesis in human cells, indicating that PNPLA1 function is conserved among mammals and indispensable for normal skin physiology. Notably, topical application of epidermal lipids from wild-type onto Pnpla1-mutant mice promoted rebuilding of the corneocyte-bound lipid envelope, indicating that supplementation of ichthyotic skin with omega-O-acylceramides might be a therapeutic approach for the treatment of skin symptoms in individuals affected by omega-O-acylceramide deficiency.
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Susanne
authors.initials: S
authors.lastname: Grond
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Eichmann
authors.affiliation: Department of Dermatology, Venerology, and Allergology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Dubrac
authors.affiliation: ZMF, Center for Medical Research, Medical University of Graz, Graz, Austria; Institute of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria; BioTechMed-Graz, Graz, Austria.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kolb
authors.affiliation: Department of Dermatology, Venerology, and Allergology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schmuth
authors.affiliation: Institute for Human Genetics, University Medical Center Freiburg, Freiburg i. Br., Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Fischer
authors.affiliation: Dermatology Service, Department of Veterans Aﬀairs Medical Center, University of California, San Francisco, California, USA.
authors.forename: Debra
authors.initials: D
authors.lastname: Crumrine
authors.affiliation: Dermatology Service, Department of Veterans Aﬀairs Medical Center, University of California, San Francisco, California, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Elias
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Guenter
authors.initials: G
authors.lastname: Haemmerle
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Zechner
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Achim
authors.initials: A
authors.lastname: Lass
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria. Electronic address: franz.radner@uni-graz.at.
authors.forename: Franz P W
authors.initials: FPW
authors.lastname: Radner
mesh_terms: D000818:Animals; D002518:Ceramides / Q000096:biosynthesis*; D007057:Ichthyosis / Q000209:etiology; D008049:Lipase / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010539:Permeability; D012867:Skin / Q000378:metabolism*; D000217:Acyltransferases; D010740:Phospholipases
chemical_list: D002518:Ceramides; D008049:Lipase; C549684:PNPLA1 protein, human; D000217:Acyltransferases; D010740:Phospholipases; C000613695:PNPLA1 protein, mouse