title: A de novo variant in the ASPRV1 gene in a dog with ichthyosis.
abstract: Ichthyoses are a heterogeneous group of inherited cornification disorders characterized by generalized dry skin, scaling and/or hyperkeratosis. Ichthyosis vulgaris is the most common form of ichthyosis in humans and caused by genetic variants in the FLG gene encoding filaggrin. Filaggrin is a key player in the formation of the stratum corneum, the uppermost layer of the epidermis and therefore crucial for barrier function. During terminal differentiation of keratinocytes, the precursor profilaggrin is cleaved by several proteases into filaggrin monomers and eventually processed into free amino acids contributing to the hydration of the cornified layer. We studied a German Shepherd dog with a novel form of ichthyosis. Comparing the genome sequence of the affected dog with 288 genomes from genetically diverse non-affected dogs we identified a private heterozygous variant in the ASPRV1 gene encoding "aspartic peptidase, retroviral-like 1", which is also known as skin aspartic protease (SASPase). The variant was absent in both parents and therefore due to a de novo mutation event. It was a missense variant, c.1052T>C, affecting a conserved residue close to an autoprocessing cleavage site, p.(Leu351Pro). ASPRV1 encodes a retroviral-like protease involved in profilaggrin-to-filaggrin processing. By immunofluorescence staining we showed that the filaggrin expression pattern was altered in the affected dog. Thus, our findings provide strong evidence that the identified de novo variant is causative for the ichthyosis in the affected dog and that ASPRV1 plays an essential role in skin barrier formation. ASPRV1 is thus a novel candidate gene for unexplained human forms of ichthyoses.
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.|DermFocus, University of Bern, Bern, Switzerland.
authors.forename: Anina
authors.initials: A
authors.lastname: Bauer
authors.affiliation: DermFocus, University of Bern, Bern, Switzerland.|Department of Clinical Research, Molecular Dermatology and Stem Cell Research, University of Bern, Bern, Switzerland.
authors.forename: Dominik P
authors.identifier: http://orcid.org/0000-0003-1352-6282
authors.initials: DP
authors.lastname: Waluk
authors.affiliation: DermFocus, University of Bern, Bern, Switzerland.|Department of Clinical Research, Molecular Dermatology and Stem Cell Research, University of Bern, Bern, Switzerland.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Galichet
authors.affiliation: DermFocus, University of Bern, Bern, Switzerland.|Dermavet, Oberentfelden, Switzerland.
authors.forename: Katrin
authors.identifier: http://orcid.org/0000-0002-9546-0768
authors.initials: K
authors.lastname: Timm
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.|DermFocus, University of Bern, Bern, Switzerland.
authors.forename: Vidhya
authors.initials: V
authors.lastname: Jagannathan
authors.affiliation: DermFocus, University of Bern, Bern, Switzerland.|Department of Clinical Research, Molecular Dermatology and Stem Cell Research, University of Bern, Bern, Switzerland.
authors.forename: Beyza S
authors.initials: BS
authors.lastname: Sayar
authors.affiliation: DermFocus, University of Bern, Bern, Switzerland.|Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.|Hubrecht Institute, CT Utrecht, The Netherlands.
authors.forename: Dominique J
authors.initials: DJ
authors.lastname: Wiener
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors.forename: Elisabeth
authors.identifier: http://orcid.org/0000-0002-3181-6083
authors.initials: E
authors.lastname: Dietschi
authors.affiliation: DermFocus, University of Bern, Bern, Switzerland.|Department of Clinical Research, Molecular Dermatology and Stem Cell Research, University of Bern, Bern, Switzerland.|Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.|Clinic for Dermatology, Inselspital, Bern University Hospital, Bern, Switzerland.
authors.forename: Eliane J
authors.initials: EJ
authors.lastname: Müller
authors.affiliation: DermFocus, University of Bern, Bern, Switzerland.|Division of Clinical Dermatology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors.forename: Petra
authors.initials: P
authors.lastname: Roosje
authors.affiliation: DermFocus, University of Bern, Bern, Switzerland.|Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors.forename: Monika M
authors.initials: MM
authors.lastname: Welle
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.|DermFocus, University of Bern, Bern, Switzerland.
authors.forename: Tosso
authors.identifier: http://orcid.org/0000-0003-0553-4880
authors.initials: T
authors.lastname: Leeb
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D004195:Disease Models, Animal; D004283:Dog Diseases / Q000201:enzymology / Q000235:genetics*; D004285:Dogs; D005260:Female; D000091344:Filaggrin Proteins; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007057:Ichthyosis / Q000201:enzymology / Q000235:genetics* / Q000662:veterinary; D007381:Intermediate Filament Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D020125:Mutation, Missense; D017422:Sequence Analysis, DNA / Q000379:methods; D017386:Sequence Homology, Amino Acid; D012867:Skin / Q000201:enzymology / Q000378:metabolism / Q000473:pathology
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D016282:Aspartic Acid Endopeptidases