{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T04:02:48Z","timestamp":1782187368409,"version":"3.54.5"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2021,8,15]],"date-time":"2021-08-15T00:00:00Z","timestamp":1628985600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,11]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>Patients with glycogen storage disease type 1a (GSD\u20101a) primarily present with life\u2010threatening hypoglycemia and display severe liver disease characterized by hepatomegaly. Despite strict dietary management, long\u2010term complications still occur, such as liver tumor development. Variations in residual glucose\u20106\u2010phosphatase (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\u20101a patients. Currently available GSD\u20101a animal models are not suitable to systematically investigate the relationship between hepatic G6PC activity and phenotypic heterogeneity or the contribution of gene\u2010gene interactions (GGIs) in the liver.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>To meet these needs, we generated and characterized a hepatocyte\u2010specific GSD\u20101a mouse model using somatic CRISPR\/CRISPR\u2010associated protein 9 (Cas9)\u2013mediated gene editing. Hepatic <jats:italic toggle=\"yes\">G6pc<\/jats:italic> 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\u2010binding protein, a transcription factor that is activated in GSD\u20101a and protects against HS under these conditions. Importantly, it also allowed for the modeling of a spectrum of GSD\u20101a phenotypes in terms of hepatic G6PC activity, fasting hypoglycemia, hypertriglyceridemia, hepatomegaly and HS.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>In conclusion, we show that somatic CRISPR\/Cas9\u2010mediated gene editing allows for the modeling of a spectrum of hepatocyte\u2010borne GSD\u20101a disease symptoms in mice and to efficiently study GGIs in the liver. This approach opens perspectives for translational research and will likely contribute to personalized treatments for GSD\u20101a and other genetic liver diseases.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.32022","type":"journal-article","created":{"date-parts":[[2021,6,22]],"date-time":"2021-06-22T14:43:30Z","timestamp":1624373010000},"page":"2491-2507","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":13,"title":["Modeling Phenotypic Heterogeneity of Glycogen Storage Disease Type 1a Liver Disease in Mice by Somatic CRISPR\/CRISPR\u2010associated protein 9\u2013Mediated Gene Editing"],"prefix":"10.1097","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4640-1830","authenticated-orcid":false,"given":"Martijn G.S.","family":"Rutten","sequence":"first","affiliation":[{"name":"Department of Pediatrics,University Medical Center Groningen,University of Groningen,Groningen,The 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