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)

作者全名："Chi, Huan; Gan, Chun; Jiang, Yaru; Chen, Dan; Qiu, Jiawen; Yang, Qing; Chen, Yaxi; Wang, Mo; Yang, Haiping; Jiang, Wei; Li, Qiu"

作者地址："[Chi, Huan; Gan, Chun; Jiang, Yaru; Chen, Dan; Qiu, Jiawen; Yang, Qing; Wang, Mo; Yang, Haiping; Jiang, Wei; Li, Qiu] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, China Int Sci & Technol Cooperat Base Child Dev &, Pediat Res Inst,Chongqing Key Lab Pediat,Children, Chongqing, Peoples R China; [Chen, Yaxi] Chongqing Med Univ, Affiliated Hosp 2, Ctr Lipid Res, Chongqing, Peoples R China; [Chen, Yaxi] Chongqing Med Univ, Affiliated Hosp 2, Key Lab Mol Biol Infect Dis, Minist Educ,Inst Viral Hepatitis,Dept Infect Dis, Chongqing, Peoples R China"

通信作者："Jiang, W; Li, Q (通讯作者)，Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, China Int Sci & Technol Cooperat Base Child Dev &, Pediat Res Inst,Chongqing Key Lab Pediat,Children, Chongqing, Peoples R China."

来源：MOLECULAR GENETICS & GENOMIC MEDICINE

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000881941100001

JCR分区：Q3

影响因子：2

年份：2022

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：chronic kidney disease; fumarylacetoacetate hydrolase; hereditary tyrosinemia type 1; mutation; whole exome sequencing

摘要："Background: 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. Methods: 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. Results: 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. Conclusions: 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."

基金机构："Multi-Center Innovation Platform for Early Development and Major Diseases of Perinatal Newborns in Different Altitude Areas; Second Batch of Funds for Chongqing Talents and Famous Teachers [020210]; National Natural Science Foundation of China [81970618]; General Project of Basic Research of Key Laboratory of Ministry of Education for Research on Child Developmental Diseases, Children's Hospital of Chongqing Medical University [GBRP-202111]"

基金资助正文："Multi-Center Innovation Platform for Early Development and Major Diseases of Perinatal Newborns in Different Altitude Areas; Second Batch of Funds for Chongqing Talents and Famous Teachers, Grant/Award Number: 020210; National Natural Science Foundation of China, Grant/Award Number: 81970618; General Project of Basic Research of Key Laboratory of Ministry of Education for Research on Child Developmental Diseases, Children's Hospital of Chongqing Medical University, Grant/Award Number: GBRP-202111"