Modeling Phenotypic Heterogeneity of Glycogen Storage Disease Type 1a Liver Disease in Mice by Somatic CRISPR/CRISPR‐associated protein 9–Mediated Gene Editing

作者：Martijn G. S. Rutten, Terry G. J. Derks, Nicolette Huijkman, Trijnie Bos, Niels Kloosterhuis, Kees C.W.A. van de Kolk, Justina Clarinda Wolters, Mirjam H. Koster, Laura Bongiovanni, Rachel Thomas, Alain de Bruin, Bart van de Sluis, Maaike H. Oosterveer · 发表于：Hepatology · 年份：2021 · DOI：10.1002/hep.32022 · 被引用次数：27 · 研究领域：Glycogen Storage Diseases and Myoclonus、Lysosomal Storage Disorders Research、Moyamoya disease diagnosis and treatment

BACKGROUND AND AIMS: Patients with glycogen storage disease type 1a (GSD-1a) primarily present with life-threatening hypoglycemia and display severe liver disease characterized by hepatomegaly. Despite strict dietary management, long-term complications still occur, such as liver tumor development. Variations in residual glucose-6-phosphatase (G6PC1) activity likely contribute to phenotypic heterogeneity in biochemical symptoms and complications between patients. However, lack of insight into the relationship between G6PC1 activity and symptoms/complications and poor understanding of the underlying disease mechanisms pose major challenges to provide optimal health care and quality of life for GSD-1a patients. Currently available GSD-1a animal models are not suitable to systematically investigate the relationship between hepatic G6PC activity and phenotypic heterogeneity or the contribution of gene-gene interactions (GGIs) in the liver. APPROACH AND RESULTS: To meet these needs, we generated and characterized a hepatocyte-specific GSD-1a mouse model using somatic CRISPR/CRISPR-associated protein 9 (Cas9)-mediated gene editing. Hepatic G6pc editing reduced hepatic G6PC activity up to 98% and resulted in failure to thrive, fasting hypoglycemia, hypertriglyceridemia, hepatomegaly, hepatic steatosis (HS), and increased liver tumor incidence. This approach was furthermore successful in simultaneously modulating hepatic G6PC and carbohydrate response element-binding protein, a transc...