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Proc Natl Acad Sci U S A. 2018 Aug 21;115(34):E8037-E8046. doi: 10.1073/pnas.1722200115. Epub 2018 Aug 6.

Zebrafish type I collagen mutants faithfully recapitulate human type I collagenopathies.

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Center for Medical Genetics Ghent, Ghent University, 9000 Ghent, Belgium.
Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, WA 98195.
Department of Genetics, Harvard Medical School, Boston, MA 02115.
Department of Orthopaedic Research, Boston Children's Hospital, Boston, MA 02115.
Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02115.
Biology Department, Research Group Evolutionary Developmental Biology, Ghent University, 9000 Ghent, Belgium.
Center for Medical Genetics Ghent, Ghent University, 9000 Ghent, Belgium;


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 a zebrafish model resembling human EDS, which harbors a number of soft connective tissues defects, typical of EDS. 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 intergenotype variability in phenotypic expressivity that closely correlates with associated OI severity. Furthermore, we demonstrate the potential for select mutations to give rise to phenotypic variability, mirroring the clinical variability associated with human disease pathology. Therefore, our work suggests the future 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.


osteogenesis imperfecta; skeletal phenomics; type I collagen; type I collagenopathies; zebrafish models

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