{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T22:52:24Z","timestamp":1777157544390,"version":"3.51.4"},"reference-count":78,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2024,8,23]],"date-time":"2024-08-23T00:00:00Z","timestamp":1724371200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["CIHR 165887"],"award-info":[{"award-number":["CIHR 165887"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010231","name":"Banting Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010231","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fonds de la recherche du Qu\u00e9bec-Sant\u00e9"},{"DOI":"10.13039\/501100021356","name":"Fondation du Grand d\u00e9fi Pierre Lavoie","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100021356","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Groupe d\u2019Aide aux Enfants Tyrosin\u00e9miques du Qu\u00e9bec"},{"name":"Fondation du CHU de Qu\u00e9bec\u2014Universit\u00e9 Laval"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,10,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Hereditary tyrosinemia type 1 is an autosomal recessive disorder caused by mutations (pathogenic variants) in fumarylacetoacetate hydrolase, an enzyme involved in tyrosine degradation. Its loss results in the accumulation of toxic metabolites that mainly affect the liver and kidneys and can lead to severe liver disease and liver cancer. Tyrosinemia type 1 has a global prevalence of approximately 1 in 100,000 births but can reach up to 1 in 1,500 births in some regions of Qu\u00e9bec, Canada. Mutating functionally related \u201cmodifier\u2019 genes (i.e. genes that, when mutated, affect the phenotypic impacts of mutations in other genes) is an emerging strategy for treating human genetic diseases. In vivo somatic genome editing in animal models of these diseases is a powerful means to identify modifier genes and fuel treatment development. In this study, we demonstrate that mutating additional enzymes in the tyrosine catabolic pathway through liver-specific genome editing can relieve or worsen the phenotypic severity of a murine model of tyrosinemia type 1. Neonatal gene delivery using recombinant adeno-associated viral vectors expressing Staphylococcus aureus Cas9 under the control of a liver-specific promoter led to efficient gene disruption and metabolic rewiring of the pathway, with systemic effects that were distinct from the phenotypes observed in whole-body knockout models. Our work illustrates the value of using in vivo genome editing in model organisms to study the direct effects of combining pathological mutations with modifier gene mutations in isogenic settings.<\/jats:p>","DOI":"10.1093\/genetics\/iyae139","type":"journal-article","created":{"date-parts":[[2024,8,24]],"date-time":"2024-08-24T00:29:03Z","timestamp":1724459343000},"source":"Crossref","is-referenced-by-count":3,"title":["In vivo dissection of the mouse tyrosine catabolic pathway with CRISPR-Cas9 identifies modifier genes affecting hereditary tyrosinemia type 1"],"prefix":"10.1093","volume":"228","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8865-8063","authenticated-orcid":false,"given":"Jean-Fran\u00e7ois","family":"Rivest","sequence":"first","affiliation":[{"name":"Centre Hospitalier Universitaire de Qu\u00e9bec Research Center and Faculty of Medicine, Laval University , Qu\u00e9bec City, QC G1V 4G2 ,","place":["Canada"]},{"name":"Universit\u00e9 Laval Cancer Research Centre , Qu\u00e9bec City, QC G1V 0A6 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophie","family":"Carter","sequence":"additional","affiliation":[{"name":"Centre Hospitalier Universitaire de Qu\u00e9bec Research Center and Faculty of Medicine, Laval University , Qu\u00e9bec City, QC G1V 4G2 ,","place":["Canada"]},{"name":"Universit\u00e9 Laval Cancer Research Centre , Qu\u00e9bec City, QC G1V 0A6 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Goupil","sequence":"additional","affiliation":[{"name":"Centre Hospitalier Universitaire de Qu\u00e9bec Research Center and Faculty of Medicine, Laval University , Qu\u00e9bec City, QC G1V 4G2 ,","place":["Canada"]},{"name":"Universit\u00e9 Laval Cancer Research Centre , Qu\u00e9bec City, QC G1V 0A6 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P\u00e9n\u00e9lope","family":"Ant\u00e9rieux","sequence":"additional","affiliation":[{"name":"Centre Hospitalier Universitaire de Qu\u00e9bec Research Center and Faculty of Medicine, Laval University , Qu\u00e9bec City, QC G1V 4G2 ,","place":["Canada"]},{"name":"Universit\u00e9 Laval Cancer Research Centre , Qu\u00e9bec City, QC G1V 0A6 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denis","family":"Cyr","sequence":"additional","affiliation":[{"name":"Medical Genetics Service, Dept. 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Pediatrics, Centre Hospitalier Universitaire de Sherbrooke (CHUS) , Sherbrooke, QC J1H 5N4 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Massimiliano","family":"Paganelli","sequence":"additional","affiliation":[{"name":"Centre Hospitalier Universitaire Sainte-Justine Research Center, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, QC H3T 1C5 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3889-9563","authenticated-orcid":false,"given":"Yannick","family":"Doyon","sequence":"additional","affiliation":[{"name":"Centre Hospitalier Universitaire de Qu\u00e9bec Research Center and Faculty of Medicine, Laval University , Qu\u00e9bec City, QC G1V 4G2 ,","place":["Canada"]},{"name":"Universit\u00e9 Laval Cancer Research Centre , Qu\u00e9bec City, QC G1V 0A6 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