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

ABSTRACT: 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.

SUBMITTER: Gistelinck C

PROVIDER: S-EPMC6112716 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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

Gistelinck Charlotte C Kwon Ronald Y RY Malfait Fransiska F Symoens Sofie S Harris Matthew P MP Henke Katrin K Hawkins Michael B MB Fisher Shannon S Sips Patrick P Guillemyn Brecht B Bek Jan Willem JW Vermassen Petra P De Saffel Hanna H Witten Paul Eckhard PE Weis MaryAnn M De Paepe Anne A Eyre David R DR Willaert Andy A Coucke Paul J PJ

Proceedings of the National Academy of Sciences of the United States of America 20180806 34

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 div ...[more]

PMID: 30082390

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

Publications

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

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