Mélanie Pichery, Anne Huchenq, Roger Sandhoff, Maella Severino-Freire, Sarra Zaafouri, Lukáš Opálka, Thierry Levade, Vanessa Soldan, Justine Bertrand-Michel, Emeline Lhuillier, Guy Serre, Annabel Maruani, Juliette Mazereeuw-Hautier, Nathalie Jonca

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 different species of ceramides skin 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 cellshell encapsulating corneocytes, the so-called cornified envelope, and most probably disorganized a disorganization of the extracellular lipid matrix. Finally, these defects in ω-O-acylceramides synthesis and cornified envelopes 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 epidermal permeability barrier function.