Rat Model for Dominant Dystrophic Epidermolysis Bullosa: Glycine Substitution Reduces Collagen VII Stability and Shows Gene-Dosage Effect

Abstract

Dystrophic epidermolysis bullosa, a severely disabling hereditary skin fragility disorder, is caused by mutations in the gene coding for collagen VII, a specialized adhesion component of the dermal-epidermal junction zone. Both recessive and dominant forms are known; the latter account for about 40% of cases. Patients with dominant dystrophic epidermolysis bullosa exhibit a spectrum of symptoms ranging from mild localized to generalized skin manifestations. Individuals with the same mutation can display substantial phenotypic variance, emphasizing the role of modifying genes in this disorder. The etiology of dystrophic epidermolysis bullosa has been known for around two decades; however, important pathogenetic questions such as involvement of modifier genes remain unanswered and a causative therapy has yet to be developed. Much of the failure to make progress in these areas is due to the lack of suitable animal models that capture all aspects of this complex monogenetic disorder. Here, we report the first rat model of dominant dystrophic epidermolysis bullosa. Affected rats carry a spontaneous glycine to aspartic acid substitution, p.G1867D, within the main structural domain of collagen VII. This confers dominant-negative interference of protein folding and decreases the stability of mutant collagen VII molecules and their polymers, the anchoring fibrils. The phenotype comprises fragile and blister-prone skin, scarring and nail dystrophy. The model recapitulates all signs of the human disease with complete penetrance. Homozygous carriers of the mutation are more severely affected than heterozygous ones, demonstrating for the first time a gene-dosage effect of mutated alleles in dystrophic epidermolysis bullosa. This novel viable and workable animal model for dominant dystrophic epidermolysis bullosa will be valuable for addressing molecular disease mechanisms, effects of modifying genes, and development of novel molecular therapies for patients with dominantly transmitted skin disease.

Congenital dystrophic epidermolysis bullosa (DEB) in Sprague Dawley rats: a case series

“…Seven of 14 pups were affected, making determination of inheritance pattern difficult, but it was unlikely to have been recessive; no attempt was made to reproduce this disease. There is also a report of a dominantly inherited, generalized form of DEB in rats . Although the histological and ultrastructural findings were similar to those observed in the present study, the severity, distribution and inheritance pattern differ.…”

Clinical and molecular investigation of Buschke‐Fischer‐Brauer in consanguineous Tunisian families

“…Homozygosity for autosomal dominant traits is relatively rare in human genetics, and its phenotypic expression is frequently much more severe than that of the heterozygous state . Recently, a rat model for dominant dystrophic epidermolysis bullosa showed that homozygous carriers of the mutation are more severely affected than heterozygous ones, demonstrating for the first time a gene‐dosage effect of mutated alleles in this disease . While this has not yet been demonstrated in animal model, we hypothesize that mutation in AAGAB gene at homozygous state could be associated with a higher disease severity that probably leads to non‐viable phenotype.…”

A nonsense mutation in theCOL7A1gene causes epidermolysis bullosa in Vorderwald cattle

“…The analysis of whole-genome re-sequencing data of 1686 cattle revealed that a nonsense mutation (rs876174537) in the COL7A1 gene segregates with EB. Sequence variants in COL7A1 cause epidermolysis bullosa in various species[19,31,32,33,34]. Interestingly, Menoud et al[19] detected the rs876174537 T-allele in three calves with dystrophic EB from the Rotes Höhenvieh cattle breed.…”