Evaluation of Two Methods for Quantification of Glycosaminoglycan Biomarkers in Newborn Dried Blood Spots from Patients with Various Mucopolysaccharidoses and GM1 Gangliosidosis

Herbst, Zackary M.; Urdaneta, Leslie; Klein, Terri; Waggoner, Christine; Liao, Hsuan-Chieh; Kubaski, Francyne; Giugliani, Roberto; Fuller, Maria; Gelb, Michael H.

doi:10.2139/ssrn.4341707

Cited by 2 publications

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“…GAG fragments (i.e., sulfated oligosaccharides) in cells were measured using a modified protocol as described [26,27]. Chondroitin disaccharide di-4S (dUA-GalNAc-4S, Biosynth) was used as the internal standard (IS).…”

Section: Glycosaminoglycan Quantificationmentioning

confidence: 99%

“…The UPLC-MS/MS analysis was carried out on a Waters TQ-S tripe quadrupole mass spectrometry coupled to an ACUIQTY Classic UPLC system. Three previously reported markers, HexN-UA-1S (MPS-IIIA), GlcNAc-6S (MPS-IIID), and GalNAc-4S (MPS-VI), were analyzed [26,27]. Two novel markers, UA-HexN-UA-2S (509.8 -> 422.7) and HexN-UA-HexNAc-UA-2S (611.4 -> 524.1), associated with MPS-I/II and MPS-IIIA, respectively, were also included.…”

Section: Glycosaminoglycan Quantificationmentioning

confidence: 99%

“…Neurons derived from iPSCs by overexpressing NGN2 have been extensively used to investigate the processes of neuronal differentiation and to create models of neurological disorders [29]. We produced MSD and isogenic control NGN2-iNs by differentiating iPSCs using established protocols [26,27]. NGN2-iNs were collected for analyses at Days 3 (D3 NGN2-iN) and 11 (D11 NGN2-iN) of differentiation in order to compare phenotypes during neuronal development.…”

Section: Differentiation Of Ipsc To Npcs and Ngn2-induced Neurons (Ng...mentioning

confidence: 99%

“…Functional deficiencies in FGE and downstream sulfatases lead to the accumulation of GAGs in MSD patient cells and animal models. To investigate whether GAGs accumulate in our MSD iPSC, NPC, and NGN-iN cell models, we quantified GAG subspecies by mass spectrometry using the endogenous, non-reducing end (NRE) biomarker method [26,27]. (Figs.…”

Section: Msd Neuronal Cells Exhibit Gag Accumulationmentioning

confidence: 99%

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A novel iPSC model reveals selective vulnerability of neurons in multiple sulfatase deficiency

Pham,

Sertori Finoti,

Cassidy

et al. 2024

Molecular Genetics and Metabolism

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Section: Glycosaminoglycan Quantificationmentioning

confidence: 99%

Section: Glycosaminoglycan Quantificationmentioning

confidence: 99%

Section: Differentiation Of Ipsc To Npcs and Ngn2-induced Neurons (Ng...mentioning

confidence: 99%

Section: Msd Neuronal Cells Exhibit Gag Accumulationmentioning

confidence: 99%

See 2 more Smart Citations

A novel iPSC model reveals selective vulnerability of neurons in multiple sulfatase deficiency

Pham,

Sertori Finoti,

Cassidy

et al. 2024

Molecular Genetics and Metabolism

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A novel iPSC model reveals selective vulnerability of neurons in Multiple Sulfatase Deficiency

Pham,

Finoti,

Cassidy

et al. 2023

Preprint

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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 iPSC line (SUMF1p.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 decreasedSUMF1gene 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 ofSUMF1. 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.

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Evaluation of Two Methods for Quantification of Glycosaminoglycan Biomarkers in Newborn Dried Blood Spots from Patients with Various Mucopolysaccharidoses and GM1 Gangliosidosis

Cited by 2 publications

References 0 publications

A novel iPSC model reveals selective vulnerability of neurons in multiple sulfatase deficiency

A novel iPSC model reveals selective vulnerability of neurons in multiple sulfatase deficiency

A novel iPSC model reveals selective vulnerability of neurons in Multiple Sulfatase Deficiency

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