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PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans


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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Figure 1: Identification of the PNPLA1 mutation in affected golden retriever dogs.
Figure 2: Identification of PNPLA1 mutations in humans with autosomal recessive congenital ichthyosis.
Figure 3: Histological analysis of skin biopsies from golden retriever dogs and human subjects.
Figure 4: Localization of wild-type PNPLA1 protein in human skin.
Figure 5: Transmission electron micrographs of fixed fresh skin biopsies from golden retriever dogs and humans.
Figure 6: Protein blotting of PNPLA1 in normal and mutant human keratinocytes, before differentiation and at 3 and 7 d after induction of differentiation.
Figure 7: Triglyceride hydrolase activity and lipid profiles of wild-type and PNPLA1-deficient human keratinocytes in cell culture.

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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).

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C.A., E.G. and F.G. designed the genetic aspects of the dog experiments. A.G., S.P., C.H., M.L.G., L.L. and S.K. performed the genetic and functional experiments for the dog studies. J. Fischer designed the human genetic analyses and supervised the functional studies on humans. E. Bourrat provided patient material and data. C.D. and G.-J.K. performed the genetic and microscopy experiments for the human studies. I.H. performed light and electron microscopy as well as immunoelectron microscopy investigations. F.D.-R. did H&E staining for histological diagnosis and investigations in dogs. S.G., F.P.W.R., R. Zimmermann and R. Zechner performed functional studies E.G., E. Bensignor, J. Fontaine and D.P., veterinarians specializing in dermatology, collected dog samples and interpreted clinical and biological data. A.T. provided 400 dog DNA samples and performed validation of the mutation in dogs. C.A., A.G., J. Fischer, F.G., C.H., M.L. and I.H.. contributed to the writing of the manuscript.

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Correspondence to Catherine André or Judith Fischer.

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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).

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