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

被引：6
|
作者：
Zhang, Ting [1 ,2 ]
Lu, Rui [3 ]
Chen, Yibing [1 ,2 ]
Yuan, Yuguo [1 ,2 ]
Song, Shaozheng [4 ]
Yan, Kunning [5 ]
Zha, Yiwen [5 ]
Zhuang, Wenwen [5 ]
Cheng, Yong [1 ,2 ]
Liang, Jingyan [5 ]
机构：
[1] Yangzhou Univ, Coll Vet Med, Yangzhou 225009, Jiangsu, Peoples R China
[2] Jiangsu Coinnovat Ctr Prevent & Control Important, Yangzhou 225009, Jiangsu, Peoples R China
[3] Jiangsu Food & Pharmaceut Sci Coll, Sch Pharm, Huaian 223003, Jiangsu, Peoples R China
[4] Taihu Univ Wuxi, Sch Nursing, Wuxi 214000, Jiangsu, Peoples R China
[5] Yangzhou Univ, Med Coll, Inst Translat Med, Yangzhou 225001, Jiangsu, Peoples R China
来源：
LIPIDS IN HEALTH AND DISEASE | 2020年 / 19卷 / 01期
关键词：
Cystathionine beta-synthase; Hyperhomocysteinemia; Dyslipidemia; Rabbits; CRISPR/Cas9; G307S mutation; PLASMA HOMOCYSTEINE CONCENTRATIONS; FOLIC-ACID SUPPLEMENTATION; BIOMEDICAL-RESEARCH; TRANSGENIC RABBIT; MOLECULAR-BASIS; RISK-FACTOR; HOMOCYSTINURIA; CHOLESTEROL; EXPRESSION; PHENOTYPE;
D O I：
10.1186/s12944-020-01394-5
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Background: Congenital hyper-homocysteinemia (HHcy) is caused by a defective cystathionine beta-synthase (CBS) gene, and is frequently associated with dyslipdemia. The aim of this study was to further elucidate the effect of mutatedCBSgene on circulating lipids using a rabbit model harboring a homozygous G307S point mutation inCBS. Methods: CRISPR/Cas9 system was used to edit theCBSgene in rabbit embryos. The founder rabbits were sequenced, and their plasma homocysteine (Hcy) and lipid profile were analyzed. Results: Six 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 oldCBS-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 theCBS-KO rabbits, and alleviated hepatic steatosis compared to the untreated animals. Conclusion: A CBSG307S rabbit model was generated that exhibited severe dyslipidemia when fed on a normal diet, indicating that G307S mutation in theCBSgene is a causative factor for dyslipidemia.
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页数：11
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