Identification of an α-l-iduronidase (IDUA) M1T mutation in a Chinese family with autosomal recessive mucopolysaccharidosis I.

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.