Crtap and p3h1 knock out zebrafish support defective collagen chaperoning as the cause of their osteogenesis imperfecta phenotype |
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| Institution: | 1. Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy;2. Department of Public Health and Experimental and Forensic Medicine, Unit of Biostatistics and Clinical Epidemiology, University of Pavia, Pavia, Italy;3. Department of Orthopedics and Sports Medicine, University of Washington, Seattle, WA, United States;4. Medical Faculty, Center for Biochemistry, Center for Molecular Medicine, University of Cologne, Cologne, Germany;5. Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;6. Department of Biology, Ghent University, Ghent, Belgium;1. School of Medicine, University of Glasgow, Glasgow, United Kingdom;2. Developmental Endocrinology Research Group, Royal Hospital for Children, Glasgow;3. Department of Sports Science, London Metropolitan University, London;4. Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom;1. Medical Faculty and University Hospital, Center of Prevention and Rehabilitation, UniReha, University of Cologne, Cologne, Germany;2. Medical Faculty and University Hospital, Department of Pediatrics, University of Cologne, Cologne, Germany;3. University Children''s Hospital Klinikum Oldenburg, Department of Neuropediatrics, Oldenburg, Germany;1. Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany;2. Laboratory of Human Genetics Bioscentia MVZ Labor Saar GMBH, Homburg, Germany;3. Radiology Center am Himmelsberg, Zweibrücken, Germany;4. Hannover Medical School (MHH), Germany;5. Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Poland |
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| Abstract: | Prolyl 3-hydroxylation is a rare collagen type I post translational modification in fibrillar collagens. The primary 3Hyp substrate sites in type I collagen are targeted by an endoplasmic reticulum (ER) complex composed by cartilage associated protein (CRTAP), prolyl 3-hydroxylase 1 (P3H1) and prolyl cis/trans isomerase B, whose mutations cause recessive forms of osteogenesis imperfecta with impaired levels of α1(I)3Hyp986. The absence of collagen type I 3Hyp in wild type zebrafish provides the unique opportunity to clarify the role of the complex in vertebrate. Zebrafish knock outs for crtap and p3h1 were generated by CRISPR/Cas9. Mutant fish have the typical OI patients’ reduced size, body disproportion and altered mineralization. Vertebral body fusions, deformities and fractures are accompanied to reduced size, thickness and bone volume. Intracellularly, collagen type I is overmodified, and partially retained causing enlarged ER cisternae. In the extracellular matrix the abnormal collagen type I assembles in disorganized fibers characterized by altered diameter. The data support the defective chaperone role of the 3-hydroxylation complex as the primary cause of the skeletal phenotype. |
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