title: Genome editing with CRISPR/Cas9 in postnatal mice corrects PRKAG2 cardiac syndrome.
abstract: PRKAG2 cardiac syndrome is an autosomal dominant inherited disease resulted from mutations in the PRKAG2 gene that encodes γ2 regulatory subunit of AMP-activated protein kinase. Affected patients usually develop ventricular tachyarrhythmia and experience progressive heart failure that is refractory to medical treatment and requires cardiac transplantation. In this study, we identify a H530R mutation in PRKAG2 from patients with familial Wolff-Parkinson-White syndrome. By generating H530R PRKAG2 transgenic and knock-in mice, we show that both models recapitulate human symptoms including cardiac hypertrophy and glycogen storage, confirming that the H530R mutation is causally related to PRKAG2 cardiac syndrome. We further combine adeno-associated virus-9 (AAV9) and the CRISPR/Cas9 gene-editing system to disrupt the mutant PRKAG2 allele encoding H530R while leaving the wild-type allele intact. A single systemic injection of AAV9-Cas9/sgRNA at postnatal day 4 or day 42 substantially restores the morphology and function of the heart in H530R PRKAG2 transgenic and knock-in mice. Together, our work suggests that in vivo CRISPR/Cas9 genome editing is an effective tool in the treatment of PRKAG2 cardiac syndrome and other dominant inherited cardiac diseases by selectively disrupting disease-causing mutations.
authors: Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China.|The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
authors: Chang
authors: C
authors: Xie
authors: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors: Ya-Ping
authors: YP
authors: Zhang
authors: The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
authors: Lu
authors: L
authors: Song
authors: Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors: Jie
authors: J
authors: Luo
authors: The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
authors: Wei
authors: W
authors: Qi
authors: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors: Jialu
authors: J
authors: Hu
authors: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors: Danbo
authors: D
authors: Lu
authors: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors: Zhen
authors: Z
authors: Yang
authors: The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
authors: Jian
authors: J
authors: Zhang
authors: Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors: Jian
authors: J
authors: Xiao
authors: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
authors: Bin
authors: B
authors: Zhou
authors: Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
authors: Jiu-Lin
authors: JL
authors: Du
authors: The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
authors: Naihe
authors: N
authors: Jing
authors: Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors: Yong
authors: Y
authors: Liu
authors: Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors: Yan
authors: Y
authors: Wang
authors: The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
authors: Bo-Liang
authors: BL
authors: Li
authors: Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors: Bao-Liang
authors: BL
authors: Song
authors: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors: Yan
authors: Y
authors: Yan
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D000818:Animals; D064113:CRISPR-Cas Systems / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D000072669:Gene Editing; D006321:Heart / Q000503:physiopathology; D006720:Homozygote; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D000094704:RNA, Guide, CRISPR-Cas Systems / Q000378:metabolism; D014927:Wolff-Parkinson-White Syndrome / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D055815:Young Adult
chemical_list: D000094704:RNA, Guide, CRISPR-Cas Systems; C526223:PRKAG2 protein, human; C576788:PRKAG2 protein, mouse; D055372:AMP-Activated Protein Kinases