Hyperhomocysteinemia and dyslipidemia in point mutation G307S of cystathionine β-synthase-deficient rabbit generated using CRISPR/Cas9

Lipids in Health and Disease

Yibing Chen¹  Yong Cheng¹  Yuguo Yuan¹  Ting Zhang¹  Yiwen Zha²  Jingyan Liang²  Wenwen Zhuang²  Kunning Yan²  Shaozheng Song³  Rui Lu⁴ 

[1]College of Veterinary Medicine, Yangzhou University, 225009, Yangzhou, Jiangsu, China

[2]Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, 225009, Yangzhou, Jiangsu, China

[3]Institute of Translational Medicine, Medical College, Yangzhou University, 225001, Yangzhou, Jiangsu, China

[4]School of Nursing, Taihu University of Wuxi, 214000, Wuxi, Jiangsu, China

[5]School of Pharmacy, Jiangsu Food & Pharmaceutical Science College, 223003, Huaian, Jiangsu, China

关键词: Cystathionine β-synthase;    Hyperhomocysteinemia;    Dyslipidemia;    Rabbits;    CRISPR/Cas9;    G307S mutation;   

DOI  :  10.1186/s12944-020-01394-5

来源: Springer

【 摘 要 】

BackgroundCongenital hyper-homocysteinemia (HHcy) is caused by a defective cystathionine β-synthase (CBS) gene, and is frequently associated with dyslipdemia. The aim of this study was to further elucidate the effect of mutated CBS gene on circulating lipids using a rabbit model harboring a homozygous G307S point mutation in CBS.MethodsCRISPR/Cas9 system was used to edit the CBS gene in rabbit embryos. The founder rabbits were sequenced, and their plasma homocysteine (Hcy) and lipid profile were analyzed.ResultsSix CBS-knockout (CBS-KO) founder lines with biallelic modifications were obtained. Mutation in CBS caused significant growth retardation and high mortality rates within 6 weeks after birth. In addition, the 6-week old CBS-KO rabbits showed higher plasma levels of Hcy, triglycerides (TG), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) compared to the age-matched wild-type (WT) controls. Histological analysis of the mutants showed accumulation of micro-vesicular cytoplasmic lipid droplets in the hepatocytes. However, gastric infusion of vitamin B and betaine complex significantly decreased the plasma levels of TG, TC and LDL-C in the CBS-KO rabbits, and alleviated hepatic steatosis compared to the untreated animals.ConclusionA CBSG307S rabbit model was generated that exhibited severe dyslipidemia when fed on a normal diet, indicating that G307S mutation in the CBS gene is a causative factor for dyslipidemia.

【 授权许可】

CC BY