title: PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans.
abstract: Ichthyoses comprise a heterogeneous group of genodermatoses characterized by abnormal desquamation over the whole body, for which the genetic causes of several human forms remain unknown. We used a spontaneous dog model in the golden retriever breed, which is affected by a lamellar ichthyosis resembling human autosomal recessive congenital ichthyoses (ARCI), to carry out a genome-wide association study. We identified a homozygous insertion-deletion (indel) mutation in PNPLA1 that leads to a premature stop codon in all affected golden retriever dogs. We subsequently found one missense and one nonsense mutation in the catalytic domain of human PNPLA1 in six individuals with ARCI from two families. Further experiments highlighted the importance of PNPLA1 in the formation of the epidermal lipid barrier. This study identifies a new gene involved in human ichthyoses and provides insights into the localization and function of this yet uncharacterized member of the PNPLA protein family.
authors.affiliation: Centre National de la Recherche Scientifique, Institut de Génétique et Développement de Rennes, Rennes, France.
authors.forename: Anaïs
authors.initials: A
authors.lastname: Grall
authors.forename: Eric
authors.initials: E
authors.lastname: Guaguère
authors.forename: Sandrine
authors.initials: S
authors.lastname: Planchais
authors.forename: Susanne
authors.initials: S
authors.lastname: Grond
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Bourrat
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hausser
authors.forename: Christophe
authors.initials: C
authors.lastname: Hitte
authors.forename: Matthieu
authors.initials: M
authors.lastname: Le Gallo
authors.forename: Céline
authors.initials: C
authors.lastname: Derbois
authors.forename: Gwang-Jin
authors.initials: GJ
authors.lastname: Kim
authors.forename: Laëtitia
authors.initials: L
authors.lastname: Lagoutte
authors.forename: Frédérique
authors.initials: F
authors.lastname: Degorce-Rubiales
authors.forename: Franz P W
authors.initials: FP
authors.lastname: Radner
authors.forename: Anne
authors.initials: A
authors.lastname: Thomas
authors.forename: Sébastien
authors.initials: S
authors.lastname: Küry
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bensignor
authors.forename: Jacques
authors.initials: J
authors.lastname: Fontaine
authors.forename: Didier
authors.initials: D
authors.lastname: Pin
authors.forename: Robert
authors.initials: R
authors.lastname: Zimmermann
authors.forename: Rudolf
authors.initials: R
authors.lastname: Zechner
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Francis
authors.initials: F
authors.lastname: Galibert
authors.forename: Catherine
authors.initials: C
authors.lastname: André
authors.forename: Judith
authors.initials: J
authors.lastname: Fischer
mesh_terms: D000328:Adult; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D018389:Codon, Nonsense; D003879:Dermatologic Agents / Q000627:therapeutic use; D004285:Dogs; D005260:Female; D005808:Genes, Recessive; D055106:Genome-Wide Association Study; D006801:Humans; D054643:INDEL Mutation; D017490:Ichthyosis, Lamellar / Q000188:drug therapy / Q000235:genetics* / Q000662:veterinary*; D008049:Lipase / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009568:Nitrendipine / Q000627:therapeutic use; D012867:Skin / Q000648:ultrastructure; D000217:Acyltransferases; D010740:Phospholipases
chemical_list: D018389:Codon, Nonsense; D003879:Dermatologic Agents; D008049:Lipase; D009568:Nitrendipine; C549684:PNPLA1 protein, human; D000217:Acyltransferases; D010740:Phospholipases