Pediatric Research Institute, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, P.R. China.
Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, P.R. China.
Mol Genet Genomic Med. 2023 Jan;11(1):e2090. doi: 10.1002/mgg3.2090. Epub 2022 Nov 12.
Hereditary tyrosinemia type 1 (HT1) is a rare inherited metabolic disease characterized by severe liver and renal dysfunction. Early identification in affected children is critical for improved treatment options and prognosis.
In this study, we identified novel compound heterozygous mutations (NM_000137: c.657delC (p.K220Rfs*12) and c.607G>A (p.A203T)) in the fumarylacetoacetate hydrolase (FAH) gene in a family. We also characterized the clinical phenotype of the proband and verified the pathogenic effects of the mutations. Furthermore, we explored the pathogenic mechanism of renal injury through renal biopsy pathology and cell-based in vitro assays. Our study aims to verify the association between novel fumarylacetoacetate hydrolase (FAH) variants and HT1, confirm the pathogenic effects of the mutations and explore the pathogenic mechanism of renal injury.
We showed these FAH mutations were inherited in an autosomal recessive manner and resulted in abnormal FAH protein expression and dysfunction, leading to fumarylacetoacetate (FAA) accumulation. The proband also showed apparent renal injury, including glomerular filtration barrier dysfunction and abnormal tubular protein reabsorption.
These observations may provide deeper insights on disease pathogenesis and identify potential therapeutic approaches for HT1 from a genetic perspective. Similarly, we hope to provide valuable information for genetic counseling and prenatal diagnostics.
遗传性酪氨酸血症 1 型（HT1）是一种罕见的遗传性代谢疾病，其特征为严重的肝肾功能障碍。早期发现受影响的儿童对于改善治疗选择和预后至关重要。
在这项研究中，我们在一个家族中鉴定出延胡索酰乙酰乙酸水解酶（FAH）基因中的新型复合杂合突变（NM_000137：c.657delC（p.K220Rfs*12）和 c.607G>A（p.A203T））。我们还对先证者的临床表型进行了特征描述，并验证了突变的致病性效应。此外，我们通过肾活检病理学和基于细胞的体外测定探索了肾损伤的致病机制。我们的研究旨在验证新型延胡索酰乙酰乙酸水解酶（FAH）变异与 HT1 的关联，确认突变的致病性效应，并探索肾损伤的致病机制。
我们表明这些 FAH 突变以常染色体隐性方式遗传，导致 FAH 蛋白表达和功能异常，从而导致延胡索酰乙酰乙酸（FAA）积聚。先证者还表现出明显的肾损伤，包括肾小球滤过屏障功能障碍和异常管状蛋白重吸收。
这些观察结果可能从遗传角度提供对疾病发病机制的更深入了解，并确定 HT1 的潜在治疗方法。同样，我们希望为遗传咨询和产前诊断提供有价值的信息。
