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Hyperhomocysteinemia and dyslipidemia in point mutation G307S of cystathionine β-synthase-deficient rabbit generated
Ting Zhang1,2, Rui Lu3, Yibing Chen1,2
1College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu, China.
Insights
A genetic mutation in the cystathionine β-synthase (CBS) gene causes congenital hyper-homocysteinemia (HHcy) and severe dyslipidemia in rabbits. Supplementation with vitamin B and betaine improved lipid levels and liver health.
Area of Science:
- Genetics
- Metabolic Disorders
- Animal Models
Background:
- Congenital hyper-homocysteinemia (HHcy) is linked to cystathionine β-synthase (CBS) gene defects and often co-occurs with dyslipidemia.
- Understanding the precise impact of CBS mutations on lipid metabolism is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the effects of a specific CBS gene mutation (G307S) on circulating lipids.
- To establish and characterize a rabbit model of HHcy-induced dyslipidemia.
Main Methods:
- CRISPR/Cas9 gene editing was employed to create CBS-knockout (CBS-KO) rabbits with a G307S mutation.
- Plasma homocysteine (Hcy) and lipid profiles (triglycerides, total cholesterol, LDL-C) were analyzed in CBS-KO and wild-type (WT) rabbits.
- Hepatic lipid accumulation was assessed via histological analysis.
Main Results:
- CBS-KO rabbits exhibited significant growth retardation, high mortality, and elevated plasma Hcy, triglycerides, total cholesterol, and LDL-C compared to WT controls.
- Histological examination revealed micro-vesicular cytoplasmic lipid droplets in the hepatocytes of CBS-KO rabbits, indicating hepatic steatosis.
- Gastric administration of vitamin B and betaine complex successfully reduced plasma lipid levels and alleviated hepatic steatosis in CBS-KO rabbits.
Conclusions:
- The generated CBSG307S rabbit model effectively recapitulates HHcy-associated dyslipidemia on a standard diet.
- The G307S mutation in the CBS gene is confirmed as a causative factor for severe dyslipidemia.
- Vitamin B and betaine supplementation show therapeutic potential for managing HHcy-related metabolic disturbances.
Background:
Congenital 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.
Methods:
CRISPR/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.
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 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.
Conclusion:
A 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.
