Duncan NRI Faculty and Staff Publications
Publication Date
3-1-2023
Journal
Journal of Inherited Metabolic Disease
DOI
10.1002/jimd.12577
PMID
36433920
PMCID
PMC10832386
PubMedCentral® Posted Date
2-1-2024
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Humans, Animals, Mice, Multiple Sulfatase Deficiency Disease, Mutation, Sulfatases, Mutation, Missense, Lysosomal Storage Diseases, Oxidoreductases Acting on Sulfur Group Donors, multiple sulfatase deficiency, MSD, SUMF1, FGE
Abstract
Multiple sulfatase deficiency (MSD) is an ultrarare lysosomal storage disorder due to deficiency of all known sulfatases. MSD is caused by mutations in the Sulfatase Modifying Factor 1 (SUMF1) gene encoding the enzyme responsible for the post-translational modification and activation of all sulfatases. Most MSD patients carry hypomorph SUMF1 variants resulting in variable degrees of residual sulfatase activities. In contrast, Sumf1 null mice with complete deficiency in all sulfatase enzyme activities, have very short lifespan with significant pre-wean lethality, owing to a challenging preclinical model. To overcome this limitation, we genetically engineered and characterized in mice two commonly identified patient-based SUMF1 pathogenic variants, namely p.Ser153Pro and p.Ala277Val. These pathogenic missense variants correspond to variants detected in patients with attenuated MSD presenting with partial enzyme deficiency and relatively less severe disease. These novel MSD mouse models have a longer lifespan and show biochemical and pathological abnormalities observed in humans. In conclusion, mice harbouring the p.Ser153Pro or the p.Ala277Val variant mimic the attenuated MSD and are attractive preclinical models for investigation of pathogenesis and treatments for MSD.
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