| First Author | Xie C | Year | 2016 |
| Journal | Cell Res | Volume | 26 |
| Issue | 10 | Pages | 1099-1111 |
| PubMed ID | 27573176 | Mgi Jnum | J:278059 |
| Mgi Id | MGI:6356120 | Doi | 10.1038/cr.2016.101 |
| Citation | Xie C, et al. (2016) Genome editing with CRISPR/Cas9 in postnatal mice corrects PRKAG2 cardiac syndrome. Cell Res 26(10):1099-1111 |
| abstractText | PRKAG2 cardiac syndrome is an autosomal dominant inherited disease resulted from mutations in the PRKAG2 gene that encodes gamma2 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. |
