PUBLICATION

Crtap and p3h1 knock out zebrafish support defective collagen chaperoning as the cause of their osteogenesis imperfecta phenotype

Authors
Tonelli, F., Cotti, S., Leoni, L., Besio, R., Gioia, R., Marchese, L., Giorgetti, S., Villani, S., Gistelinck, C., Wagener, R., Kobbe, B., Larionova, D., Fiedler, I.A.K., Busse, B., Eyre, D., Rossi, A., Witten, P.E., Forlino, A.
ID
ZDB-PUB-200403-81
Date
2020
Source
Matrix biology : journal of the International Society for Matrix Biology   90: 40-60 (Journal)
Registered Authors
Forlino, Antonella, Witten, P. Eckhard
Keywords
Cartilage associated protein, Prolyl 3-hydroxylase, Prolyl 3-hydroxylation complex, Recessive osteogenesis imperfecta, Zebrafish skeletal disease models, Collagen type I
MeSH Terms
  • Animals
  • CRISPR-Cas Systems
  • Collagen Type I/metabolism*
  • Collagen Type II/metabolism*
  • Cyclophilins/genetics
  • Disease Models, Animal
  • Extracellular Matrix Proteins/genetics*
  • Gene Knockout Techniques
  • Hydroxylation
  • Osteogenesis Imperfecta/genetics*
  • Osteogenesis Imperfecta/metabolism
  • Phenotype
  • Prolyl Hydroxylases/chemistry
  • Prolyl Hydroxylases/genetics*
  • Zebrafish
  • Zebrafish Proteins/chemistry
  • Zebrafish Proteins/genetics
PubMed
32173581 Full text @ Matrix Biol.
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping