The compound heterozygous mutations of c.607G>a and c.657delC in the FAH gene are associated with renal damage with hereditary tyrosinemia type 1 (HT1).
The compound heterozygous mutations of c.607G>a and c.657delC in the FAH gene are associated with renal damage with hereditary tyrosinemia type 1 (HT1).
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DOI：
10.1002/mgg3.2090
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发表时间：
2023-01
影响因子：
2
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中科院分区：
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遗传性酪氨酸血症1型（HT1）是一种罕见的遗传性代谢疾病，以严重的肝肾功能障碍为特征。对受影响儿童的早期识别对于改善治疗方案和预后至关重要。在这项研究中，我们在一个家族中发现了新的复合杂合突变（NM_000137: c.657delC （p.K220Rfs*12）和c.607G>A (p.A203T)）。我们还描述了先证者的临床表型，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实验探讨了肾损伤的致病机制。本研究旨在验证新型富马酰乙酸水解酶（FAH）变异与HT1的相关性，确认突变的致病作用，探讨肾损伤的致病机制。我们发现这些FAH突变以常染色体隐性方式遗传，导致FAH蛋白表达异常和功能障碍，导致富马酰乙酸（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小管蛋白重吸收异常。这些观察结果可能为HT1的发病机制提供更深入的见解，并从遗传学角度确定潜在的治疗方法。同样，我们希望为遗传咨询和产前诊断提供有价值的信息。本研究发现了新的复合杂合突变(NM_000137: c.657delC （p. k220rfs *12）和NM_000137: c.607G>A（p. k220rfs *12）。患者FAH基因中的A203T))与HT1有关。我们发现这些FAH突变以常染色体隐性方式遗传，导致FAH蛋白表达异常和功能障碍，导致富马酰乙酸（FAA）积累。我们成功地解释了FAA代谢调节失败和肝肾功能异常。这些观察结果可能为HT1的发病机制提供更深入的见解，并从遗传学角度确定潜在的治疗方法。同样，我们希望为遗传咨询和产前诊断提供有价值的信息。
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. This study demonstrated the novel compound heterozygous mutations (NM_000137: c.657delC (p.K220Rfs*12) and NM_000137: c.607G>A(p.A203T)) in FAH gene in a patient were responsible for HT1. 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. We have successfully accounted for the failure on regulation of FAA metabolism and abnormal liver and kidney function. 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.
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影响因子：
16.2
作者：
Araki S;Haneda M;Koya D;Sugaya T;Isshiki K;Kume S;Kashiwagi A;Uzu T;Maegawa H
通讯作者：
Maegawa H
影响因子：
13.6
作者：
Amsellem, Sabine;Gburek, Jakub;Kozyraki, Renata
通讯作者：
Kozyraki, Renata
影响因子：
1.9
作者：
Kawabata, Kazuo;Kido, Jun;Yoshida, Takanobu;Matsumoto, Shirou;Nakamura, Kimitoshi
通讯作者：
Nakamura, Kimitoshi
影响因子：
19.6
作者：
Luijerink, MC;van Beurden, EACM;van den Berg, IET
通讯作者：
van den Berg, IET
影响因子：
82.9
作者：
通讯作者：
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