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

Tytuł:: Hyperhomocysteinemia and dyslipidemia in point mutation G307S of cystathionine β-synthase-deficient rabbit generated using CRISPR/Cas9.
Autorzy:: Zhang T; College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu, China.; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, Jiangsu, China.
Lu R; School of Pharmacy, Jiangsu Food & Pharmaceutical Science College, Huaian, 223003, Jiangsu, China.
Chen Y; College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu, China.; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, Jiangsu, China.
Yuan Y; College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu, China.; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, Jiangsu, China.
Song S; School of Nursing, Taihu University of Wuxi, Wuxi, 214000, Jiangsu, China.
Yan K; Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, Jiangsu, China.
Zha Y; Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, Jiangsu, China.
Zhuang W; Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, Jiangsu, China.
Cheng Y; College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu, China. .; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, Jiangsu, China. .
Liang J; Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, Jiangsu, China. .
Źródło:: Lipids in health and disease [Lipids Health Dis] 2020 Oct 14; Vol. 19 (1), pp. 224. Date of Electronic Publication: 2020 Oct 14.
Typ publikacji:: Journal Article
Język:: English
Imprint Name(s):: Original Publication: [London] : BioMed Central, 2002-
MeSH Terms:: CRISPR-Cas Systems*
Cystathionine beta-Synthase/*genetics
Dyslipidemias/*genetics
Hyperhomocysteinemia/*genetics
Animals ; Betaine/pharmacology ; Body Weight/genetics ; Disease Models, Animal ; Female ; Gene Knockout Techniques ; Hyperlipidemias/drug therapy ; Hyperlipidemias/genetics ; Liver/pathology ; Male ; Point Mutation ; Rabbits ; Vitamin B Complex/pharmacology
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Grant Information:: No. 2016YFE0126000 National Key Research and Development Program of China
Contributed Indexing:: Keywords: CRISPR/Cas9; Cystathionine β-synthase; Dyslipidemia; G307S mutation; Hyperhomocysteinemia; Rabbits
Substance Nomenclature:: 12001-76-2 (Vitamin B Complex)
3SCV180C9W (Betaine)
EC 4.2.1.22 (Cystathionine beta-Synthase)
Entry Date(s):: Date Created: 20201015 Date Completed: 20210812 Latest Revision: 20210812
Update Code:: 20240105
PubMed Central ID:: PMC7560309
DOI:: 10.1186/s12944-020-01394-5
PMID:: 33054837
: Czasopismo naukowe

Pełny tekst

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 CBS G307S 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.

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