A homozygous LAMB3 frameshift variant in junctional epidermolysis bullosa-affected Bleu du Maine sheep.

Abstract

Epidermolysis bullosa (EB) is a group of inherited skin disorders characterized by skin fragility and blistering. Here, four Bleu du Maine lambs, sired by one ram, were diagnosed with EB very early in life. Due to the severity of the clinical signs, the lambs had to be euthanized. The affected lambs exhibited hoof sloughing and multiple ulcerations on the head, oral cavity, skin over the joints, and the ruminal pillars. Histopathology showed abrupt subepidermal clefts, epidermal detachment directly above the basal membrane, and ulcerations consistent with junctional EB (JEB). Two cases underwent whole-genome sequencing (WGS) to identify the genetic cause. Genomic analyses with the hypothesis of autosomal recessive inheritance identified the most likely pathogenic homozygous 1-bp deletion in the LAMB3 gene (NC_056065.1:g.73166198delG). Recessive forms of JEB in humans and dogs are caused by variants in LAMB3 gene, which encodes β3 subunit of laminin 332, a critical component of the epidermal basal membrane. The ovine frameshift variant putatively introduces a premature stop codon and disrupts the donor splice site of exon 20. The variant allele was homozygous in both sequenced cases and heterozygous in three unaffected close relatives and was absent in 1075 unrelated control sheep of various other breeds. This study highlights the importance of genetic investigation in veterinary diagnostics of and represents the first report of a LAMB3-related recessive EB in sheep. The findings enable genetic testing to inform breeding strategies and provide a second spontaneous large animal model for LAMB3-related JEB in humans.