Suppression of the Idua-W402X mutation in an MPS I-H mouse

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DESCRIPTION (provided by applicant): The mucopolysaccharidosis (MRS) diseases are a broad class of genetic disorders characterized by the excessive accumulation of glycosaminoglycans (GAGs) within the lysosomes of various tissues. Among these disorders, MPS I-H is the most severe form of an autosomal recessive lysosomal storage disease caused by a deficiency of a-L-iduronidase (encoded by the IDUA gene), which participates in the degradation of GAGs within the lysosome. Recent studies have shown that certain aminoglycosides and other pharmacological agents have the ability to suppress stop mutations that cause a number of genetic diseases [For review, see Keeling and Bedwell, Current Pharmacogenomics 3: 259-269, (2005)]. Consistent with these previous results, we found that the aminoglycoside gentamicin can suppress the IDUA Q70X and W402X premature stop mutations (carried by ~70% of MPS I-H patients) and restore enough a-L-iduronidase activity to normalize GAG levels in cultured primary fibroblasts derived from an MPS I-H patient [Keeling et al., Human Molecular Genetics 10: 291-299 (2001)]. To further explore this novel therapeutic treatment, we recently succeeded in constructing an /c/tya-W402X knock-in mouse in which the /DLW-W402X premature stop mutation found in MPS I-H patients was introduced into the corresponding position in the mouse Idua gene. This new mouse model will allow us to test the hypothesis that the suppression of premature stop mutations and/or nonsense-mediated mRNA decay (NMD) can restore enough a-L-iduronidase activity to correct the disease manifestations of MPS I-H in vivo. To test this hypothesis and further develop and evaluate the utility of this treatment strategy, we propose the following specific aims: Specific Aim #1: Characterize the phenotype associated with a homozygous /dt/a-W402X mouse. Specific Aim #2: Determine whether compounds that suppress premature stop mutations can restore significant a-L-iduronidase activity in a homozygous ldua-\N4Q2X mouse. Specific Aim #3: Examine the relationship between NMD and suppression of the /dua-W402X mutation.