Mouse models for dominant dystrophic epidermolysis bullosa carrying common human point mutations recapitulate the human disease

Abstract

Heterozygous missense mutations in the human COL7A1 gene – coding for collagen VII – lead to the rare, dominantly inherited skin disorder dominant dystrophic epidermolysis bullosa (DDEB), which is characterised by skin fragility, blistering, scarring and nail dystrophy. To better understand the pathophysiology of DDEB and develop more effective treatments, suitable mouse models for DDEB are required but to date none have existed. We identified the two most common COL7A1 mutations in DDEB patients (p.G2034R and p.G2043R) and used CRISPR-Cas9 to introduce the corresponding mutations into mouse Col7a1 (p.G2028R and p.G2037R). Dominant inheritance of either of these two alleles results in a phenotype that closely resembles that seen in DDEB patients. Specifically, mice carrying these alleles show recurrent blistering that is first observed transiently around the mouth and paws in the early neonatal period and then again around the digits from 5-10 weeks of age. Histologically, the mice show micro-blistering and reduced collagen VII immunostaining. Biochemically, collagen VII from these mice displays reduced thermal stability, which we also observed to be the case for DDEB patients carrying the analogous mutations. Unlike previous rodent models of epidermolysis bullosa, which frequently show early lethality and severe disease, these mouse models, which to our knowledge are the first for DDEB, show no reduction in growth and survival, and – together with a relatively mild phenotype – represent a practically and ethically tractable tool for better understanding and treating epidermolysis bullosa. This article has an associated First Person interview with the first author of the paper.

Challenges of Gene Editing Therapies for Genodermatoses

“…Furthermore, the immunodeficiency allowed for the trial of human cell therapies in mice models without triggering an immune response, which would prove valuable for ex vivo gene therapies [152]. For gene editing therapies, it is also important that the mutations in mouse models match mutations found in human patients, which was achieved with DDEB mutations in 2021 [153]. In the future, this would allow gene editing technologies to be trialled on mouse models as part of pre-clinical work to see the systemic effects of gene editing tools.…”

Dystrophic Epidermolysis Bullosa: Secondary Disease Mechanisms and Disease Modifiers

“…Because of the rarity of the disease and the large mutational spectra of RDEB, it is challenging to identify factors in detail and on a mechanistic level in the human system. Here, the use of smallanimal models greatly facilitates the discovery and functional assessment of disease-modulating mechanisms, as spontaneous and genetically engineered small-animal models with identical with COL7A1 mutations display diversity in phenotypic presentations (Nyström et al, 2013a(Nyström et al, , 2015Smith et al, 2021).…”

First person – Blake Smith

“… ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Blake Smith is first author on ‘ Mouse models for dominant dystrophic epidermolysis bullosa carrying common human point mutations recapitulate the human disease ’, published in DMM. Blake is a PhD student in the lab of Ken Pang at Murdoch Children's Research Institute, Parkville, Australia, currently investigating the rare genetic skin disease epidermolysis bullosa utilising a novel mouse model.…”