ALOXE3 missense variant in a Chihuahua with autosomal recessive ichthyosis

Abstract

Ichthyoses are a heterogenous group of inherited disorders that are characterized by excessive scale formation on the skin. We investigated a Chihuahua with severe scaling since age 12 weeks. The scaling was generalized and involved the entire body and legs. The paw pads were mildly hyperkeratotic. The clinical features together with histopathological findings in skin biopsies were compatible with non-epidermolytic ichthyosis. To identify a potential genetic cause of the ichthyosis, we sequenced the genome of the affected dog and compared the data to 1567 control genomes. Filtering for private variants identified a homozygous missense variant in ALOXE3, XP_038392720.1:p.(Gly460Asp). ALOXE3 is a known candidate gene for ichthyosis in humans and encodes arachidonate epidermal lipoxygenase 3. The enzyme is involved in the production of a functional corneocyte lipid envelope, an essential component of the epidermal barrier. Pathogenic variants in ALOXE3 have been described in human patients with autosomal recessive congenital ichthyosis. We assume that the identified missense variant in the affected Chihuahua of this study impairs the normal function of the ALOXE3 protein and the formation of a functioning corneocyte lipid envelope, which ultimately leads to a disorder of cornification that manifests as ichthyosis. To the best of our knowledge, this is the first report of a spontaneous ALOXE3 variant in domestic animals.