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.

Two MC1R loss‐of‐function alleles in cream‐coloured Australian Cattle Dogs and white Huskies

“…Single nucleotide and small indel variants with respect to the CanFam3.1 canine reference genome assembly were called as described (Bauer et al . ). The variants were compared to previously obtained genome sequences.…”

A frameshift variant in the COL5A1 gene in a cat with Ehlers‐Danlos syndrome

“…The methodology was previously described (Bauer et al . ). We identified 93 private homozygous and 2339 private heterozygous protein‐changing variants (Table ).…”

Ichthyosis molecular fingerprinting shows profound TH17 skewing and a unique barrier genomic signature

“…Data derived from animal or human models suggest abnormalities in cornification, lipid homeostasis, and keratinocyte adhesion/desquamation among various ichthyoses, implying shared defects in barrier architecture. [18][19][20][21][22][23][24][25][26] Human skin and blood studies have been limited to a few patients or select ichthyosis subtypes and have shown abnormalities in lipid, cornified envelope (CE), and/or other differentiation measures. 18,[27][28][29][30][31][32][33][34][35][36][37][38][39][40] Several observations link ichthyoses, particularly Netherton syndrome (NS), to atopic dermatitis (AD), which is marked by epidermal barrier defects and immune dysregulation.…”