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Zebrafish type I collagen mutants faithfully recapitulate human type I collagenopathies

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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.
Keywords
skeletal phenomics, type I collagen, type I collagenopathies, zebrafish models, osteogenesis imperfecta, PHENOTYPIC VARIABILITY, HELICAL DOMAIN, GENE-FUNCTION, FIN FORMATION, BONE, MUTATIONS, PROTEIN, MODEL, DEFECTS

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MLA
Gistelinck, Charlotte et al. “Zebrafish Type I Collagen Mutants Faithfully Recapitulate Human Type I Collagenopathies.” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 115.34 (2018): E8037–E8046. Print.
APA
Gistelinck, C., Kwon, R. Y., Malfait, F., Symoens, S., Harris, M. P., Henke, K., Hawkins, M. B., et al. (2018). Zebrafish type I collagen mutants faithfully recapitulate human type I collagenopathies. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 115(34), E8037–E8046.
Chicago author-date
Gistelinck, Charlotte, Ronald Y Kwon, Fransiska Malfait, Sofie Symoens, Matthew P Harris, Katrin Henke, Michael B Hawkins, et al. 2018. “Zebrafish Type I Collagen Mutants Faithfully Recapitulate Human Type I Collagenopathies.” Proceedings of the National Academy of Sciences of the United States of America 115 (34): E8037–E8046.
Chicago author-date (all authors)
Gistelinck, Charlotte, Ronald Y Kwon, Fransiska Malfait, Sofie Symoens, Matthew P Harris, Katrin Henke, Michael B Hawkins, Shannon Fisher, Patrick Sips, Brecht Guillemyn, Jan Willem Bek, Petra Vermassen, Hanna De Saffel, Paul Witten, MaryAnn Weis, Anne De Paepe, David R Eyre, Andy Willaert, and Paul Coucke. 2018. “Zebrafish Type I Collagen Mutants Faithfully Recapitulate Human Type I Collagenopathies.” Proceedings of the National Academy of Sciences of the United States of America 115 (34): E8037–E8046.
Vancouver
1.
Gistelinck C, Kwon RY, Malfait F, Symoens S, Harris MP, Henke K, et al. Zebrafish type I collagen mutants faithfully recapitulate human type I collagenopathies. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 2018;115(34):E8037–E8046.
IEEE
[1]
C. Gistelinck et al., “Zebrafish type I collagen mutants faithfully recapitulate human type I collagenopathies,” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 115, no. 34, pp. E8037–E8046, 2018.
@article{8580246,
  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.},
  author       = {Gistelinck, Charlotte and Kwon, Ronald Y and Malfait, Fransiska and Symoens, Sofie and Harris, Matthew P and Henke, Katrin and Hawkins, Michael B and Fisher, Shannon and Sips, Patrick and Guillemyn, Brecht and Bek, Jan Willem and Vermassen, Petra and De Saffel, Hanna and Witten, Paul and Weis, MaryAnn and De Paepe, Anne and Eyre, David R and Willaert, Andy and Coucke, Paul},
  issn         = {0027-8424},
  journal      = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
  keywords     = {skeletal phenomics,type I collagen,type I collagenopathies,zebrafish models,osteogenesis imperfecta,PHENOTYPIC VARIABILITY,HELICAL DOMAIN,GENE-FUNCTION,FIN FORMATION,BONE,MUTATIONS,PROTEIN,MODEL,DEFECTS},
  language     = {eng},
  number       = {34},
  pages        = {E8037--E8046},
  title        = {Zebrafish type I collagen mutants faithfully recapitulate human type I collagenopathies},
  url          = {http://dx.doi.org/10.1073/pnas.1722200115},
  volume       = {115},
  year         = {2018},
}

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