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. [ABSTRACT FROM AUTHOR]