Abstract
Background: Mucopolysaccharidosis type I-Hurler (MPS1-H) is a severe genetic lysosomal storage disorder due to loss-of-function mutations in the IDUA gene. The subsequent complete deficiency of alpha l-iduronidase enzyme is directly responsible of a progressive accumulation of glycosaminoglycans (GAG) in lysosomes which affects the functions of many tissues. Consequently, MPS1 is characterized by systemic symptoms (multiorgan dysfunction) including respiratory and cardiac dysfunctions, skeletal abnormalities and early fatal neurodegeneration. Methods: To understand mechanisms underlying MPS1 neuropathology, we generated induced pluripotent stem cells (iPSC) from a MPS1-H patient with loss-of-function mutations in both IDUA alleles. To avoid variability due to different genetic background of iPSC, we established an isogenic control iPSC line by rescuing IDUA expression by a lentivectoral approach. Results: Marked differences between MPS1-H and IDUA-corrected isogenic controls were observed upon neural differentiation. A scratch assay revealed a strong migration defect of MPS1-H cells. Also, there was a massive impact of IDUA deficiency on gene expression (340 genes with an FDR < 0.05). Conclusions: Our results demonstrate a hitherto unknown connection between lysosomal degradation, gene expression and neural motility, which might account at least in part for the phenotype of MPS1-H patients.
Highlights
Mucopolysaccharidosis type I-Hurler (MPS1-H) is a rare inherited metabolic disorder caused by loss-of-function mutations in the IDUA gene leading to the complete deficiency of alpha-L-iduronidase, the enzyme involved in the degradation of glycosaminoglycans (GAGs) [1,2]
The UBI-IDUA-PGK-BSD lentivector allowed a constitutive expression of α-L-iduronidase enzyme (IDUAα) since IDUA is upon ubiquitin (UBI) promotor
The rescue MPS1-H fibroblasts was first validated by measuring the activity of α-L-iduronidase enzyme (IDUAα)
Summary
Mucopolysaccharidosis type I-Hurler (MPS1-H) is a rare inherited metabolic disorder caused by loss-of-function mutations in the IDUA gene leading to the complete deficiency of alpha-L-iduronidase, the enzyme involved in the degradation of glycosaminoglycans (GAGs) [1,2]. The mucopolysaccharidosis type I-Hurler (MPS1-H), which is the most prevalent phenotype and the most severe form of MPS1, is characterized by critical musculoskeletal alterations, cardiovascular, respiratory affections and serious neurological dysfunctions [3,4,5,6] Despite this broad phenotypic spectrum [2], the progression of MPS1-H pathological process is insufficiently advanced at birth to detect any phenotypic alteration. Results: Marked differences between MPS1-H and IDUA-corrected isogenic controls were observed upon neural differentiation
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