Animal Models of Ehlers-Danlos Syndromes: Phenotype, Pathogenesis, and Translational Potential.

Robin Vroman,Anne-Marie Malfait,Fransiska Malfait,Delfien Syx,Rachel E Miller

doi:10.3389/fgene.2021.726474

Robin Vroman, Anne-Marie Malfait + Show 3 more

Open Access

https://doi.org/10.3389/fgene.2021.726474

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Abstract

The Ehlers–Danlos syndromes (EDS) are a group of heritable connective tissues disorders mainly characterized by skin hyperextensibility, joint hypermobility and generalized tissue fragility. Currently, 14 EDS subtypes each with particular phenotypic features are recognized and are caused by genetic defects in 20 different genes. All of these genes are involved in the biosynthesis and/or fibrillogenesis of collagens at some level. Although great progress has been made in elucidating the molecular basis of different EDS subtypes, the pathogenic mechanisms underlying the observed phenotypes remain poorly understood, and consequentially, adequate treatment and management options for these conditions remain scarce. To date, several animal models, mainly mice and zebrafish, have been described with defects in 14 of the 20 hitherto known EDS-associated genes. These models have been instrumental in discerning the functions and roles of the corresponding proteins during development, maturation and repair and in portraying their roles during collagen biosynthesis and/or fibrillogenesis, for some even before their contribution to an EDS phenotype was elucidated. Additionally, extensive phenotypical characterization of these models has shown that they largely phenocopy their human counterparts, with recapitulation of several clinical hallmarks of the corresponding EDS subtype, including dermatological, cardiovascular, musculoskeletal and ocular features, as well as biomechanical and ultrastructural similarities in tissues. In this narrative review, we provide a comprehensive overview of animal models manifesting phenotypes that mimic EDS with a focus on engineered mouse and zebrafish models, and their relevance in past and future EDS research. Additionally, we briefly discuss domestic animals with naturally occurring EDS phenotypes. Collectively, these animal models have only started to reveal glimpses into the pathophysiological aspects associated with EDS and will undoubtably continue to play critical roles in EDS research due to their tremendous potential for pinpointing (common) signaling pathways, unveiling possible therapeutic targets and providing opportunities for preclinical therapeutic interventions.

Highlights

The Ehlers–Danlos syndromes (EDS) comprise a group of rare heritable connective tissue disorders, clinically hallmarked by skin hyperextensibility and fragility, generalized joint hypermobility, abnormal wound healing, easy bruising, and widespread connective tissue friability (Malfait et al, 2017)
These findings laid the basis for the revised International Classification of the Ehlers–Danlos Syndromes, published in 2017, which provides a regrouping of EDS based on the underlying genetic defect and affected pathways (Malfait et al, 2017)
The heart was morphologically normal, but immunohistochemical analysis revealed increased deposition of type I and III collagen in mitral and aortic valves and ventricular myocardium, supposedly as a compensatory mechanism for disturbed fibrillogenesis due to reduced type V collagen content (Lincoln et al, 2006). These findings indicate the importance of type V collagen in vascular and cardiac structure, integrity and/or function, cardiovalvular problems are rarely of clinical significance and severe or life-threatening arterial manifestations are only sporadically observed in Classical EDS (cEDS) patients (Bowen et al, 2017; Malfait, 2018; Angwin et al, 2020; Colman et al, 2021)

Summary

Introduction

The Ehlers–Danlos syndromes (EDS) comprise a group of rare heritable connective tissue disorders, clinically hallmarked by skin hyperextensibility and fragility, generalized joint hypermobility, abnormal wound healing, easy bruising, and widespread connective tissue friability (Malfait et al, 2017). No overt joint hypermobility, another major feature of human cEDS, was described in Col5a1+/− mice (Wenstrup et al, 2006), biomechanical analysis of the flexor digitorum longus (FDL) and patellar tendons showed reduced tensile strength, suggesting increased elasticity.

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Conclusion