Abstract
In a highly inbred Australian Shepherd litter, three of the five puppies developed widespread ulcers of the skin, footpads, and oral mucosa within the first weeks of life. Histopathological examinations demonstrated clefting of the epidermis from the underlying dermis within or just below the basement membrane, which led to a tentative diagnosis of junctional epidermolysis bullosa (JEB) with autosomal recessive inheritance. Endoscopy in one affected dog also demonstrated separation between the epithelium and underlying tissue in the gastrointestinal tract. As a result of the severity of the clinical signs, all three dogs had to be euthanized. We sequenced the genome of one affected puppy and compared the data to 73 control genomes. A search for private variants in 37 known candidate genes for skin fragility phenotypes revealed a single protein-changing variant, LAMB3:c.1174T>C, or p.Cys392Arg. The variant was predicted to change a conserved cysteine in the laminin β3 subunit of the heterotrimeric laminin-322, which mediates the binding of the epidermal basement membrane to the underlying dermis. Loss-of-function variants in the human LAMB3 gene lead to recessive forms of JEB. We confirmed the expected co-segregation of the genotypes in the Australian Shepherd family. The mutant allele was homozygous in two genotyped cases and heterozygous in three non-affected close relatives. It was not found in 242 other controls from the Australian Shepherd breed, nor in more than 600 other controls. These data suggest that LAMB3:c.1174T>C represents the causative variant. To the best of our knowledge, this study represents the first report of a LAMB3-related JEB in domestic animals.
Highlights
When a human or animal, usually at or soon after birth, develops erosions and epithelial sloughing on the mucosae, areas of friction, and extremities, a genetic disorder of skin fragility is to be considered
All variants in the affected dog 2d), the basement3,111,811 discerned at the base of the clefts, suggesting the diagnosis of junctional epidermolysis bullosa (JEB)
In the affected Australian Shepherds described in this study, the age of lesion onset, as well as the presence of ulceration in the oral cavity and pressure points on the limbs with a loss of claws, all suggested the clinical diagnosis of a skin fragility disorder, of which Epidermolysis Bullosa (EB) is the most representative disease group in domestic animals and humans (Table S1)
Summary
When a human or animal, usually at or soon after birth, develops erosions and epithelial sloughing on the mucosae, areas of friction, and extremities, a genetic disorder of skin fragility is to be considered. Genes 2020, 11, 1055 the epidermis [1] In this reclassification, four main categories of inherited “classical” EB are proposed, which reflect the differences in the level of cleavage in the basement membrane zone [1]. Four main categories of inherited “classical” EB are proposed, which reflect the differences in the level of cleavage in the basement membrane zone [1] Included in this reclassification are four new categories of epidermal disorders of skin fragility associated with 20 possibly mutated genes, namely: peeling skin disorders, erosive skin fragility disorders, keratinopathic ichthyoses, and pachyonychia congenita [1]. A single syndromic connected tissue disorder with (dermal) skin fragility associated with PLOD3 variants and a lysyl hydroxylase-3 deficiency was included in this group of diseases [1].
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