PUBLICATION
Identification of an α-l-iduronidase (IDUA) M1T mutation in a Chinese family with autosomal recessive mucopolysaccharidosis I
- Authors
- Liu, D., Jiang, Z., Deng, L., Li, H., Jiang, H.
- ID
- ZDB-PUB-230623-36
- Date
- 2023
- Source
- Annals of the New York Academy of Sciences 1526(1): 114-125 (Journal)
- Registered Authors
- Keywords
- IDUA, apoptosis, mucopolysaccharidosis, zebrafish
- MeSH Terms
-
- Animals
- East Asian People
- Humans
- Iduronidase/genetics
- Iduronidase/metabolism
- Mucopolysaccharidosis I*/genetics
- Mucopolysaccharidosis I*/pathology
- Mutation
- Zebrafish/genetics
- PubMed
- 37347427 Full text @ Ann N Y Acad Sci
Citation
Liu, D., Jiang, Z., Deng, L., Li, H., Jiang, H. (2023) Identification of an α-l-iduronidase (IDUA) M1T mutation in a Chinese family with autosomal recessive mucopolysaccharidosis I. Annals of the New York Academy of Sciences. 1526(1):114-125.
Abstract
Mucopolysaccharidoses (MPS) are a group of rare congenital metabolic disorders caused by the deficiency or low activity of enzymes required for glycosaminoglycans degradation. Mutations in the α-l-iduronidase gene (IDUA) are associated with mucopolysaccharidosis type I (MPS I). Our study here aims to identify an MPS-related gene mutation in a typical patient with MPS and to further explore the possible pathogenic mechanism. We identified a homozygous c. 2T>C (p.M1T) change in IDUA as the pathogenic mutation in this individual (both parents were identified as carriers of the mutation), with IDUA enzyme activity significantly decreased. We further established an MPS I-related zebrafish model using IDUA-specific morpholino (MO) to suppress gene expression, and found that IDUA-MO zebrafish exhibited characteristic disease phenotypes with deficiency of IDUA. Transcriptome profiling of zebrafish larvae revealed 487 genes that were significantly altered when IDUA was depleted. TP53 signaling and LC3/GABARAP family protein-mediated autophagy were significantly upregulated in IDUA-MO zebrafish larvae. Moreover, leukotriene A4 hydrolase-mediated arachidonic acid metabolism was also upregulated. Introduction of wild-type human IDUA mRNA rescued developmental defects and aberrant signaling in IDUA-MO zebrafish larvae. In conclusion, our study provides potential therapeutic targets for the treatment of MPS I.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping