Phenotypic characterisation of the Mucopolysaccharidosis Type I (MPSI) Idua-W392X mouse model reveals increased anxiety-related traits in female mice.

Abstract

Mucopolysaccharidosis Type I (MPSI) is a rare inherited lysosomal storage disease that arises due to mutations in the IDUA gene. Defective alpha-L-iduronidase (IDUA) enzyme is unable to break down glucosaminoglycans (GAGs) within the lysosomes and, as a result, there is systemic accumulation of undegraded products in lysosomes throughout the body leading to multi-system disease. Here, we characterised the skeletal/craniofacial, neuromuscular and behavioural outcomes of the MPSI Idua-W392X mouse model. We demonstrate that Idua-W392X mice have gross craniofacial abnormalities, showed signs of kyphosis, and show signs of hypoactivity compared to wild-type mice. X-ray imaging analysis revealed significantly shorter and wider tibias and femurs, significantly wider snouts, increased skull width and significantly thicker zygomatic arch bones in Idua-W392X female mice compared to wild-type mice at 9 and 10.5months of age. Idua-W392X mice display decreased muscle strength, especially in the forelimbs, which is already apparent from 3months of age. Female Idua-W392X mice display hypoactivity in the open-field test from 9months of age and anxiety-like behaviour at 10months of age. As these behaviours have been identified in Hurler children, the MPSI Idua-W392X mouse model may be important for the investigation of new therapeutic approaches for MPSI-Hurler.