New preprint: Zebrafish type I collagen mutants faithfully recapitulate human type I collagenopathies

We are part of a consortium of researchers investigating Osteogenesis Imperfecta (OI) in zebrafish. Our new preprint performing deep phenotyping in zebrafish models of OI has been published on bioarxiv:
Zebrafish type I collagen mutants faithfully recapitulate human type I collagenopathies

Charlotte GistelinckRonald Y KwonFransiska MalfaitSofie SymoensMatthew P HarrisKatrin HenkeShannon FisherPatrick SipsBrecht GuillemynJan Willem BeckPetra VermassenHanna De SaffelMaryAnn WeisAnne De PaepeDavid R EyreAndy WillaertPaul Coucke

The type I collagenopathies are a group of heterogeneous connective tissue disorders, that are caused by mutations in the genes encoding type I collagen and include specific forms of Osteogenesis Imperfecta (OI) and the Ehlers-Danlos syndrome (EDS). These disorders present with a broad disease spectrum and large clinical variability of which the underlying genetic basis is still poorly understood. In this study, we systematically analyzed skeletal phenotypes in a large set of zebrafish, with diverse mutations in the genes encoding type I collagen, representing different genetic forms of human OI, and the first zebrafish model of human EDS, which harbors characteristic defects in the soft connective tissues. Furthermore, we provide insight into how zebrafish and human type I collagen are compositionally and functionally related, which is relevant in the interpretation of human type I collagen related disease models. Our studies reveal a high degree of inter-genotype variability in phenotypic expressivity that closely correlates with associated OI severity. Further, we demonstrate the potential for select mutations to give rise to variable phenotypic penetrance, mirroring the clinical variability associated with human disease pathology. Therefore, our work suggests the potential for zebrafish to aid in identifying unknown genetic modifiers and mechanisms underlying the phenotypic variability in OI and related disorders. This will improve diagnostic strategies and enable the discovery of new targetable pathways for pharmacological intervention.

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