title: PNPLA1 defects in patients with autosomal recessive congenital ichthyosis and KO mice sustain PNPLA1 irreplaceable function in epidermal omega-O-acylceramide synthesis and skin permeability barrier.
abstract: Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of monogenic genodermatoses that encompasses non-syndromic disorders of keratinization. The pathophysiology of ARCI has been linked to a disturbance in epidermal lipid metabolism that impaired the stratum corneum function, leading to permeability barrier defects. Functional characterization of some genes involved in ARCI contributed to the identification of molecular actors involved in epidermal lipid synthesis, transport or processing. Recently, PNPLA1 has been identified as a gene causing ARCI. While other members of PNPLA family are key elements in lipid metabolism, the function of PNPLA1 remained unclear. We identified 5 novel PNPLA1 mutations in ARCI patients, mainly localized in the putative active enzymatic domain of PNPLA1. To investigate Pnpla1 biological role, we analysed Pnpla1-deficient mice. KO mice died soon after birth from severe epidermal permeability defects. Pnpla1-deficient skin presented an important impairment in the composition and organization of the epidermal lipids. Quantification of epidermal ceramide species highlighted a blockade in the production of ω-O-acylceramides with a concomitant accumulation of their precursors in the KO. The virtually loss of ω-O-acylceramides in the stratum corneum was linked to a defective lipid coverage of the resistant pericellular shell encapsulating corneocytes, the so-called cornified envelope, and most probably disorganized the extracellular lipid matrix. Finally, these defects in ω-O-acylceramides synthesis and cornified envelope formation were also evidenced in the stratum corneum from PNPLA1-mutated patients. Overall, our data support that PNPLA1/Pnpla1 is a key player in the formation of ω-O-acylceramide, a crucial process for the epidermal permeability barrier function.
authors.affiliation: Unité Différenciation Epithéliale et Autoimmunité Rhumatoïde (UDEAR), UMR 1056 Inserm - Université de Toulouse, Place du Dr Baylac, Hôpital Purpan, TSA 40031, F-31059 Toulouse, Cedex 9, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Pichery
authors.affiliation: Unité Différenciation Epithéliale et Autoimmunité Rhumatoïde (UDEAR), UMR 1056 Inserm - Université de Toulouse, Place du Dr Baylac, Hôpital Purpan, TSA 40031, F-31059 Toulouse, Cedex 9, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Huchenq
authors.affiliation: Lipid Pathobiochemistry Group within the Department of Cellular and Molecular Pathology, German CanCer Research Centre (DKFZ), 69120 Heidelberg, Germany.|Centre for Applied Sciences at Technical Universities (ZAFH)-Applied Biomedical Mass Spectrometry (ABIMAS), 68163 Mannheim, Germany.
authors.forename: Roger
authors.initials: R
authors.lastname: Sandhoff
authors.affiliation: Unité Différenciation Epithéliale et Autoimmunité Rhumatoïde (UDEAR), UMR 1056 Inserm - Université de Toulouse, Place du Dr Baylac, Hôpital Purpan, TSA 40031, F-31059 Toulouse, Cedex 9, France.|Reference Centre for Rare Skin Diseases, Larrey Hospital, Toulouse, France.
authors.forename: Maella
authors.initials: M
authors.lastname: Severino-Freire
authors.affiliation: Unité Différenciation Epithéliale et Autoimmunité Rhumatoïde (UDEAR), UMR 1056 Inserm - Université de Toulouse, Place du Dr Baylac, Hôpital Purpan, TSA 40031, F-31059 Toulouse, Cedex 9, France.
authors.forename: Sarra
authors.initials: S
authors.lastname: Zaafouri
authors.affiliation: Department of Inorganic and Organic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové 50005, Czech Republic.
authors.forename: Lukáš
authors.initials: L
authors.lastname: Opálka
authors.affiliation: Laboratoire de Biochimie Métabolique, IFB, CHU Purpan, 31059 Toulouse, France; INSERM UMR 1037, CRCT, Université Paul Sabatier Toulouse-III, 31062 Toulouse, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Levade
authors.affiliation: Plateforme de Microscopie Électronique Intégrative (METi), CBI (Centre de Biologie Intégrative) CNRS FR3743, Bat IBCG, F-31062, Toulouse, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Soldan
authors.affiliation: MetaToul-Lipidomic Core Facility, Inserm U1048, Toulouse, France.
authors.forename: Justine
authors.initials: J
authors.lastname: Bertrand-Michel
authors.affiliation: Unité Différenciation Epithéliale et Autoimmunité Rhumatoïde (UDEAR), UMR 1056 Inserm - Université de Toulouse, Place du Dr Baylac, Hôpital Purpan, TSA 40031, F-31059 Toulouse, Cedex 9, France.|Plateau de Génomique GeT-Purpan, Genotoul, Hôpital Purpan, Place du Dr Baylac - TSA 40031, F-31059 Toulouse, Cedex 9, France.
authors.forename: Emeline
authors.initials: E
authors.lastname: Lhuillier
authors.affiliation: Unité Différenciation Epithéliale et Autoimmunité Rhumatoïde (UDEAR), UMR 1056 Inserm - Université de Toulouse, Place du Dr Baylac, Hôpital Purpan, TSA 40031, F-31059 Toulouse, Cedex 9, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Serre
authors.affiliation: University François Rabelais Tours, 37000 Tours, CHRU Tours, Department of Dermatology, Unit of Paediatric Dermatology, 37044 Tours, France.
authors.forename: Annabel
authors.initials: A
authors.lastname: Maruani
authors.affiliation: Unité Différenciation Epithéliale et Autoimmunité Rhumatoïde (UDEAR), UMR 1056 Inserm - Université de Toulouse, Place du Dr Baylac, Hôpital Purpan, TSA 40031, F-31059 Toulouse, Cedex 9, France.|Reference Centre for Rare Skin Diseases, Larrey Hospital, Toulouse, France.
authors.forename: Juliette
authors.initials: J
authors.lastname: Mazereeuw-Hautier
authors.affiliation: Unité Différenciation Epithéliale et Autoimmunité Rhumatoïde (UDEAR), UMR 1056 Inserm - Université de Toulouse, Place du Dr Baylac, Hôpital Purpan, TSA 40031, F-31059 Toulouse, Cedex 9, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Jonca
mesh_terms: D000368:Aged; D000818:Animals; D002518:Ceramides / Q000378:metabolism; D002648:Child; D004817:Epidermis / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D017490:Ichthyosis, Lamellar / Q000235:genetics*; D008049:Lipase / Q000235:genetics* / Q000378:metabolism*; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; 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