Categories: Integument (skin) phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 150310 (gene) , 226700 (trait) , 226650 (trait)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2020

Species-specific symbol: JEB

Species-specific description: In epidermolysis bullosa (EB), the epidermis easily detaches from the underlying dermis. Currently four subtypes of EB are distinguished: EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB) and Kindler EB. At the time of preparing this entry, 16 different EB genes were known in human genetics (Has et al. 2020).

Molecular basis: Kiener et al. (2020) studied an Australian Shepherd family consisting of the parents, three affected and two unaffected puppies. The litter was the result of a father-daughter mating. Analysis of whole genome sequence data from one affected puppy and 73 healthy control dogs was performed. The analysis was focused on 37 functional candidate genes known to cause human skin fragility phenotypes. The analysis yielded a single private homozygous protein-changing variant in the 37 studied candidate genes in the affected puppy. This missense variant, LAMB3:p.Cys392Arg, was predicted to disrupt a conserved disulfide bridge in the third LE domain of laminin beta 3, a subunit of the heterotrimeric laminin-332. The extracellular laminin-322 is a component of hemidesmosomes and provides a physical link between the epidermis and the underlying dermis. Laminin-332 binds to integrin alpha6-beta4 located in the membrane of basal keratinocytes and to collagen type VII secreted by dermal fibroblasts. The genotypes at LAMB3:p.Cys392Arg perfectly cosegregated with the disease phenotype in the studied family. The mutant allele was not found in more than 200 unrelated controls from the Australian Shepherd breed (Kiener et al. 2020).

The mutant LAMB3 allele probably retains some residual function as the affected dogs show a JEB of intermediate severity. Complete LAMB3 null alleles lead to severe JEB with neonatal lethality in other species (Kiener et al. 2020).

Clinical features: Affected puppies developed widespread ulcers of the skin, footpads, and oral mucosa within the first weeks of life. The average weight was about half that of their unaffected siblings. Due to the severity of the phenotype affected dogs were euthanized between 4 and 7.5 months of age (Kiener et al. 2020). The skin lesions were not seen at birth and developed only during the first weeks of life. This led to the classification of a JEB of intermediate severity (Kiener et al. 2020).

Pathology: "Microscopically, the skin and mucosal biopsy samples all exhibited limited-to-widespread epidermal detachment, and ulcers were covered with serocellular crusts; inflammation was sparse in non-ulcerated areas. In some sections, the basement membrane could be discerned at the base of the clefts, thus suggesting the diagnosis of JEB." Epithelial detachment was also noted in an intestinal biopsy taken from duodenum during endoscopy of one of the affected puppies (Kiener et al. 2020).

Breed: Australian Shepherd.

Associated gene: