A novel iPSC model reveals selective vulnerability of neurons in multiple sulfatase deficiency
Issued Date
2024-01-01
Resource Type
ISSN
10967192
eISSN
10967206
Scopus ID
2-s2.0-85181251862
Journal Title
Molecular Genetics and Metabolism
Rights Holder(s)
SCOPUS
Bibliographic Citation
Molecular Genetics and Metabolism (2024)
Suggested Citation
Pham V., Sertori Finoti L., Cassidy M.M., Maguire J.A., Gagne A.L., Waxman E.A., French D.L., King K., Zhou Z., Gelb M.H., Wongkittichote P., Hong X., Schlotawa L., Davidson B.L., Ahrens-Nicklas R.C. A novel iPSC model reveals selective vulnerability of neurons in multiple sulfatase deficiency. Molecular Genetics and Metabolism (2024). doi:10.1016/j.ymgme.2023.108116 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/95534
Title
A novel iPSC model reveals selective vulnerability of neurons in multiple sulfatase deficiency
Author's Affiliation
The Children's Hospital of Philadelphia
Universitätsmedizin Göttingen
Faculty of Medicine Ramathibodi Hospital, Mahidol University
University of Washington
University of Pennsylvania Perelman School of Medicine
Fraunhofer Institute for Translational Medicine and Pharmacology – Translational Neuroinflammation and Automated Microscopy
Universitätsmedizin Göttingen
Faculty of Medicine Ramathibodi Hospital, Mahidol University
University of Washington
University of Pennsylvania Perelman School of Medicine
Fraunhofer Institute for Translational Medicine and Pharmacology – Translational Neuroinflammation and Automated Microscopy
Corresponding Author(s)
Other Contributor(s)
Abstract
Multiple sulfatase deficiency (MSD) is an ultra-rare, inherited lysosomal storage disease caused by mutations in the gene sulfatase modifying factor 1 (SUMF1). MSD is characterized by the functional deficiency of all sulfatase enzymes, leading to the storage of sulfated substrates including glycosaminoglycans (GAGs), sulfolipids, and steroid sulfates. Patients with MSD experience severe neurological impairment, hearing loss, organomegaly, corneal clouding, cardiac valve disease, dysostosis multiplex, contractures, and ichthyosis. Here, we generated a novel human model of MSD by reprogramming patient peripheral blood mononuclear cells to establish an MSD induced pluripotent stem cell (iPSC) line (SUMF1 p.A279V). We also generated an isogenic control iPSC line by correcting the pathogenic variant with CRISPR/Cas9 gene editing. We successfully differentiated these iPSC lines into neural progenitor cells (NPCs) and NGN2-induced neurons (NGN2-iN) to model the neuropathology of MSD. Mature neuronal cells exhibited decreased SUMF1 gene expression, increased lysosomal stress, impaired neurite outgrowth and maturation, reduced sulfatase activities, and GAG accumulation. Interestingly, MSD iPSCs and NPCs did not exhibit as severe of phenotypes, suggesting that as neurons differentiate and mature, they become more vulnerable to loss of SUMF1. In summary, we demonstrate that this human iPSC-derived neuronal model recapitulates the cellular and biochemical features of MSD. These cell models can be used as tools to further elucidate the mechanisms of MSD pathology and for the development of therapeutics.