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

[lamellar ichthyosis]

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 PNPLA 1 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 PNPLA 1 in six individuals with ARCI from two families . Further experiments highlighted the importance of PNPLA 1 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 .