loading page

A CRISPR-engineered swine model of COL2A1 deficiency recapitulates altered early skeletal developmental defects in humans
  • +10
  • Boyan Zhang,
  • Chenyu Wang,
  • Yue Zhang,
  • Yuan Jiang,
  • Yanguo Qin,
  • Daxin Pang,
  • Guizhen Zhang,
  • He Liu,
  • Zicong Xie,
  • Hongming Yuan,
  • Hongsheng Ouyang,
  • Jincheng Wang,
  • Xiaochun Tang
Boyan Zhang
Jilin University Second Hospital
Author Profile
Chenyu Wang
Jilin University First Hospital
Author Profile
Yue Zhang
Jilin University First Hospital
Author Profile
Yuan Jiang
College of Animal Sciences, Jilin University
Author Profile
Yanguo Qin
Jilin University Second Hospital
Author Profile
Daxin Pang
Jilin University
Author Profile
Guizhen Zhang
Jilin University Second Hospital
Author Profile
He Liu
Jilin University Second Hospital
Author Profile
Zicong Xie
College of Animal Sciences, Jilin University
Author Profile
Hongming Yuan
Jilin University
Author Profile
Hongsheng Ouyang
Jilin University
Author Profile
Jincheng Wang
Jilin University Second Hospital
Author Profile
Xiaochun Tang
Jilin University
Author Profile

Abstract

Loss-of-function mutations in the COL2A1 gene were recently described as a cause of type II collagenopathy, a major subgroup of genetic skeletal diseases. However, the pathogenic mechanisms associated with COL2A1 mutations remain unclear, and there are few large-mammal models of these diseases. In this study, we established a swine model carrying COL2A1 mutations using CRISPR/Cas9 and somatic cell nuclear transfer technologies. Animals mutant for COL2A1 exhibited severe skeletal dysplasia characterized by shortened long bones, abnormal vertebrae, depressed nasal bridge, and cleft palate. Importantly, COL2A1 mutant piglets suffered tracheal collapse, which was almost certainly the cause of their death shortly after birth. In conclusion, we have demonstrated for the first time that overt and striking skeletal dysplasia occurring in human patients can be recapitulated in large transgenic mammals. This model underscores the importance of employing large animals as models to investigate the pathogenesis and potential therapeutics of skeletal diseases.