Heterozygous <i>ASPRV1</i> frameshift variant in a Pembroke Welsh Corgi with ichthyosis

Ichthyoses comprise a large, heterogeneous group of inherited cornification disorders. They are characterized by generalized scaly and hyperkeratotic skin (Oji et al., 2010). In humans, over 69 genes have been associated with different forms of ichthyosis, grouped into non-syndromic ichthyoses with the phenotypic expression of the disorder only seen in the skin, and syndromic ichthyoses that show additional organ involvement (Gutiérrez-Cerrajero et al., 2023; Uitto et al., 2020). Further subdivision into epidermolytic and non-epidermolytic ichthyoses is based on the presence or absence of light microscopic findings of vacuoles and lysis of keratinocytes (Mauldin, 2013). In dogs, several breed-specific ichthyoses have been described, and, to date, causal variants in nine different genes have been identified (Affolter et al., 2022; Bauer et al., 2017; Briand et al., 2019; Casal et al., 2017; Credille et al., 2005, 2009; Grall et al., 2012; Kiener et al., 2022; Kiener, Åhman, et al., 2023; Kiener, Castilla, et al., 2023; Metzger et al., 2015). These genes are mainly involved in the biosynthesis, metabolism, and transport of lipids required for skin barrier function or the intracellular protein network responsible for the integrity of skin structure (Gutiérrez-Cerrajero et al., 2023). A 6-month-old Pembroke Welsh Corgi was presented with non-pruritic severe scaling (large 5–10-mm scales; Figure 1a), hyperkeratotic paw pads (Figure 1b), and fish-skin like flakes and erythema in friction areas (Figure 1c), present since shortly after birth. Histological examination of biopsies taken from haired skin and paw pads showed prominent compact to lamellar orthokeratotic hyperkeratosis (Figure 1d). The observed changes were compatible with non-epidermolytic ichthyosis. We performed Illumina short-read whole-genome sequencing at 26× coverage on genomic DNA isolated from leukocytes to investigate potential causal genetic variants. The data were processed as previously described (Jagannathan et al., 2019) with respect to the genome reference assembly UU_Cfam_GSD_1.0. Subsequent comparison of the whole-genome sequencing data of the affected dog to 960 genetically diverse canine genomes (Table S1) revealed 76 heterozygous and eight homozygous protein-changing private variants (Table S2). Among them was a heterozygous two base-pair deletion variant in the ichthyosis candidate gene ASPRV1, XM_038551592.1:c.594_595del or Chr10:NC_049231.1:69888722_69888723del, leading to a frameshift and altering 48% of the wildtype protein sequence, XP_038407520.1:p.(Leu199Argfs*342). The predicted mutant protein contains 539 compared to 381 amino acids in the wildtype protein. ASPRV1 encodes the retroviral-like aspartic protease 1, which is responsible for cleavage of the multimeric profilaggrin into filaggrin monomers, which are essential for the structural integrity of the outermost, cornified layer of the epidermis. The identified c.594_595del frameshift variant is most likely to be the result of a de novo mutation event and probably leads to a complete loss of ASPRV1 function. A whole-genome sequencing approach in a Pembroke Welsh Corgi with clinically and histopathologically diagnosed ichthyosis enabled us to identify a candidate causative variant in ASPRV1. The gene has previously been reported to cause an autosomal dominant form of ichthyosis in a German Shepherd and in human patients (Bauer et al., 2017; Boyden et al., 2020). Our study highlights the potential of precision medicine for investigating genodermatoses in veterinary medicine. Sarah Kiener: Conceptualization; investigation; visualization; writing – original draft; writing – review and editing. Susanne Åhman: Conceptualization; investigation; visualization; writing – original draft; writing – review and editing. Robert Cikota: Investigation; writing – review and editing. Vidhya Jagannathan: Data curation; writing – review and editing. Sohvi Blatter: Investigation; visualization; writing – original draft; writing – review and editing. Iva Cvitas: Investigation; writing – review and editing. Sara Soto: Investigation; visualization; writing – original draft; writing – review and editing. Tosso Leeb: Conceptualization; funding acquisition; visualization; writing – original draft; writing – review and editing. We thank the dog owner for providing samples and information. Furthermore, we are grateful to the Next Generation Sequencing Platform of the University of Bern for performing whole-genome sequencing experiments and the Interfaculty Bioinformatics Unit of the University of Bern for providing the computational infrastructure. We acknowledge the DBVDC consortium, the Dog10K genomes project and all researchers who deposited dog whole genome sequencing data into public databases. This study was funded by grant 310030_200354 from the Swiss National Science Foundation. Open access funding provided by Universitat Bern. The authors declare no conflict of interest. The accession numbers of 961 dog genomes are listed in Table S1. Private variants in the sequenced Pembroke Welsh Corgi affected with ichthyosis with respect to 960 control geneomes are listed in Table S2. Table S1. Table S2. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Topic: Skin and Cellular Biology Research
Subfield: Cell Biology
Field: Biochemistry, Genetics and Molecular Biology
Domain: Life Sciences