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@ARTICLE{Pichery:124272,
      author       = {M. Pichery and A. Huchenq and R. Sandhoff$^*$ and M.
                      Severino-Freire and S. Zaafouri and L. Opálka and T. Levade
                      and V. Soldan and J. Bertrand-Michel and E. Lhuillier and G.
                      Serre and A. Maruani and J. Mazereeuw-Hautier and N. Jonca},
      title        = {{PNPLA}1 defects in patients with autosomal recessive
                      congenital ichthyosis and {KO} mice sustain {PNPLA}1
                      irreplaceable function in epidermal omega-{O}-acylceramide
                      synthesis and skin permeability barrier.},
      journal      = {Human molecular genetics},
      volume       = {26},
      number       = {10},
      issn         = {1460-2083},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DKFZ-2017-01168},
      pages        = {1787 - 1800},
      year         = {2017},
      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.},
      cin          = {G131},
      ddc          = {570},
      cid          = {I:(DE-He78)G131-20160331},
      pnm          = {317 - Translational cancer research (POF3-317)},
      pid          = {G:(DE-HGF)POF3-317},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:28369476},
      doi          = {10.1093/hmg/ddx079},
      url          = {https://inrepo02.dkfz.de/record/124272},
}