Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree.

Autor: Guo Z; Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Medical Genetics Institute of Henan Province, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450000, China. zhenglongguo@zzu.edu.cn.; School of Medicine, People's Hospital of Henan University, Henan University, Zhengzhou, 450000, China. zhenglongguo@zzu.edu.cn., Huo D; Bone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, Institute of Hematology, Zhejiang Province Engineering Research Center for Stem Cell and Immunity Therapy, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310003, China., Shao Y; The First Affiliated Hospital of Zhengzhou University School, Zhengzhou, 450000, China., Yang W; Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Medical Genetics Institute of Henan Province, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450000, China.; School of Medicine, People's Hospital of Henan University, Henan University, Zhengzhou, 450000, China., Wang J; Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Medical Genetics Institute of Henan Province, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450000, China.; School of Medicine, People's Hospital of Henan University, Henan University, Zhengzhou, 450000, China., Zhang Y; Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Medical Genetics Institute of Henan Province, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450000, China.; School of Medicine, People's Hospital of Henan University, Henan University, Zhengzhou, 450000, China., Xiao H; Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Medical Genetics Institute of Henan Province, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450000, China.; School of Medicine, People's Hospital of Henan University, Henan University, Zhengzhou, 450000, China., Hao B; Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Medical Genetics Institute of Henan Province, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450000, China. haobt123@zzu.edu.cn.; Department of Immunology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China. haobt123@zzu.edu.cn.; Henan Eye Institute, Henan Academy of Innovations in Medical Science, Zhengzhou, Henan, 450000, China. haobt123@zzu.edu.cn., Liao S; Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Medical Genetics Institute of Henan Province, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450000, China. ychslshx@henu.edu.cn.; School of Medicine, People's Hospital of Henan University, Henan University, Zhengzhou, 450000, China. ychslshx@henu.edu.cn.
Jazyk: angličtina
Zdroj: Orphanet journal of rare diseases [Orphanet J Rare Dis] 2024 Nov 25; Vol. 19 (1), pp. 435. Date of Electronic Publication: 2024 Nov 25.
DOI: 10.1186/s13023-024-03465-7
Abstrakt: Background: Cellular iron metabolism is essential for maintaining various biological processes in organisms, and this is influenced by the function of iron-responsive element-binding protein 2 (IRP2), encoded by the IREB2 gene. Since 2019, three cases of a genetic neurodegenerative syndrome resulting from compound heterozygous mutations in IREB2 have been documented, highlighting the crucial role of IRP2 in regulating iron metabolism homeostasis. This study aims to investigate the molecular basis in a single proband born to non-consanguineous healthy parents, presenting with severe psychomotor developmental abnormalities and microcytic anemia.
Methods: Trio-whole exome sequencing (WES) was applied to identify the disease-causing gene in an 8-month-old male patient from China. In silico tools were used to predict the pathogenicity of the identified variants, and in vitro functional studies were performed to evaluate the molecular mechanism.
Results: WES identified novel biallelic variants, c.1111 A > G (P.Ile371Val) and c.2477 A > T (P.Asp826Val), in the IREB2 gene, which encodes the iron metabolism-related protein, IRP2. Functional studies revealed that c.2477 A > T resulted in a significant degradation of IRP2, which led to the misregulation of intracellular ferric iron.
Conclusions: We report the identification of the first functional domain associated with the degradation of IRP2. The biallelic variants that affect protein degradation likely underlie the pathogenesis of the IRP2-related neurodegenerative disorder. Moreover, the use of proteasome inhibitors can potentially restore the expression of IRP2, highlighting a promising therapeutic target for patients with IRP2deficiency.
Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the Ethics Committee of Henan Provincial People’s Hospital, China, with No. 2020-75. Consent for publication: The parents have signed informed consent and agreed to publish the data included in this article. Competing interests: The authors report no conflict of interest.
(© 2024. The Author(s).)
Databáze: MEDLINE
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