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.
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We thank A.S. Lequarré, an excellent coordinator for the European FP7 LUPA project, A. Boland and D. Zelenika for the genotyping performed at CNG (Evry, France); dermatologists, especially F. Caux, and Généthon, for patient DNA processing; J. Abadie (AMaROC research unit, Oniris, Ecole Nationale Vétérinaire de Nantes, France) and practitioners T. Bord, X. Langon, P. Prelaud, M.D. Vaillant, A. Muller and other veterinarians for providing us with clinical data and samples, as well as dog owners and breeders, especially J. Robidou, B. Facq, V. d'Alcantara and C. de Vinck. We thank P. Roosje and T. Leeb (University of Bern, Switzerland) for providing six Swiss golden retriever samples. We thank A. Fautrel and P. Bellaud, from the histopathology platform H2P2, IFR140 Biogenouest, (Rennes, France), M.D. Vignon-Pennamen from the anatomopathology laboratory of Saint Louis Hospital (Paris, France) and M. Werner from the Institute of Pathology at the University Hospital of Freiburg (Freiburg, Germany) who kindly provided paraffin human skin sections, as well as the Vébiotel laboratory (Arcueil, France) for dog sample biochemical analyses. We are grateful to G. Queney (Antagene, Lyon, France) and P. Quignon, G. Rabut and E. Watrin (Institut de Génétique et Développement de Rennes, France) for helpful discussions. Finally, we warmly thank S. Cure from Genoscope (Evry, France) for her several careful readings and English corrections and her kind availability, as well as D. Morris-Rosendahl (Institute for Human Genetics, Freiburg, Germany). This study was supported by CNRS, the European Commission (FP7-LUPA, GA-201370). R. Zechner and R. Zimmermann were supported by the FWF F30 SFB Lipotox, Z136 Wittgenstein, the GEN-AU project GOLD by the Austrian Ministry of Science and Research and FFG. I.H. was supported by the NIRK Network (German BMBF 01GM0904).
CNRS and Université Rennes 1 (including C.A., E.G. and S.P.) have applied for an international patent (Catherine André et al., PCT/EP2010/067569) covering the use of the canine PNPLA1 mutation for the genetic screening of ichthyosis in dogs. The Antagene laboratory has the international license for providing the ichthyosis DNA test in dogs.
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Grall, A., Guaguère, E., Planchais, S. et al. PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans. Nat Genet 44, 140–147 (2012). https://doi.org/10.1038/ng.1056
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