Abstract：
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.
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.
摘要：
背景：遗传性酪氨酸血症1型（HT1）是一种罕见的遗传性代谢疾病，其特征是严重的肝和肾功能障碍。早期识别受影响儿童对于改善治疗选择和预后至关重要。
方法：在本研究中，我们鉴定了新的复合杂合突变（NM_000137：c.657delC（p。K220Rfs*12）和c.607G>A（p。A203T））在一个家族的富马酸乙酰乙酸水解酶（FAH）基因中。我们还对先证者的临床表型进行了表征，并验证了突变的致病作用。此外，我们通过肾活检病理和基于细胞的体外检测来探索肾损伤的致病机制。我们的研究旨在验证新型富马酸乙酰乙酸水解酶（FAH）变体与HT1之间的关联，确认突变的致病作用并探讨肾损伤的致病机制。
结果：我们发现这些FAH突变以常染色体隐性遗传方式遗传，并导致FAH蛋白表达异常和功能障碍，导致富马酸乙酰乙酸酯（FAA）积累。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肾小管蛋白重吸收异常。
结论：这些观察可能为疾病发病机制提供更深入的见解，并从遗传角度确定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。
方法：在本研究中，我们鉴定了新的复合杂合突变（NM_000137：c.657delC（p。K220Rfs*12）和c.607G>A（p。A203T））在一个家族的富马酸乙酰乙酸水解酶（FAH）基因中。我们还对先证者的临床表型进行了表征，并验证了突变的致病作用。此外，我们通过肾活检病理和基于细胞的体外检测来探索肾损伤的致病机制。我们的研究旨在验证新型富马酸乙酰乙酸水解酶（FAH）变体与HT1之间的关联，确认突变的致病作用并探讨肾损伤的致病机制。
结果：我们发现这些FAH突变以常染色体隐性遗传方式遗传，并导致FAH蛋白表达异常和功能障碍，导致富马酸乙酰乙酸酯（FAA）积累。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肾小管蛋白重吸收异常。
结论：这些观察可能为疾病发病机制提供更深入的见解，并从遗传角度确定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。
