1 型遗传性酪氨酸血症是一种常染色体隐性遗传疾病，由延胡索酰乙酰乙酸水解酶（一种参与酪氨酸降解的酶）突变（致病变异）引起。它的损失导致有毒代谢物的积累，主要影响肝脏和肾脏，并可能导致严重的肝病和肝癌。 1 型酪氨酸血症的全球患病率约为十万分之一，但在加拿大魁北克省的某些地区，这一比例可能高达千分之一。突变功能相关的“修饰”基因（即，当突变时，影响其他基因突变的表型影响的基因）是治疗人类遗传疾病的新兴策略。这些疾病的动物模型中的体内体细胞基因组编辑是识别修饰基因和促进治疗开发的有力手段。在这项研究中，我们证明通过肝脏特异性基因组编辑突变酪氨酸分解代谢途径中的其他酶可以减轻或恶化1型酪氨酸血症小鼠模型的表型严重程度。使用表达金黄色葡萄球菌的重组腺相关病毒载体进行新生儿基因递送Cas9在肝脏特异性启动子的控制下导致有效的基因破坏和通路的代谢重新布线，其系统效应与全身敲除模型中观察到的表型不同。我们的工作说明了在模型生物体中使用体内基因组编辑来研究等基因环境中病理突变与修饰基因突变相结合的直接影响的价值。© 作者 2024。由牛津大学出版社代表遗传学会出版美国的。

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 Québec, Canada. Mutating functionally related 'modifier' 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.© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America.