Generation of human induced pluripotent stem cell line UNIGEi001-A from a 2-years old patient with Mucopolysaccharidosis type IH disease

Lito, Silvin; Burda, Patricie; Baumgartner, Matthias R.; Sloan‐Béna, Frédérique; Táncos, Zsuzsanna; Kobolák, Julianna; Dinnyés, András; Krause, Karl-Heinz; Marteyn, Antoine

doi:10.1016/j.scr.2019.101604

Cited by 6 publications

(9 citation statements)

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“…The MPS1-H iPSC line was generated from the reprogramming of dermal fibroblasts, isolated from a skin biopsy of 2-year-old male MPS1-H child [30]. The loss-of-function of IDUAα have been associated to the presence of two distinct mutations distributed on the two alleles of the IDUA gene: NM_000203.5(IDUA):c.1073_1093del (p.His358_Thr364del) and NM_000203.4(IDUA):c.1205 G>A (p.Trp402Ter).…”

Section: Establishment and Characterization Of Mps1-h Ipsc Linementioning

confidence: 99%

“…The loss-of-function of IDUAα have been associated to the presence of two distinct mutations distributed on the two alleles of the IDUA gene: NM_000203.5(IDUA):c.1073_1093del (p.His358_Thr364del) and NM_000203.4(IDUA):c.1205 G>A (p.Trp402Ter). All details concerning reprogramming, cell culture maintenance and characterization of the line have been reported in a previous study [30]. The isogenic control iPSC line, resulting from the transduction of MPS1-H iPSC line with a lentivector allowing the expression of normal IDUA gene, have been characterized in similar experimental conditions.…”

Section: Establishment and Characterization Of Mps1-h Ipsc Linementioning

confidence: 99%

“…The ability of the lentivector to rescue α-l-iduronidase enzyme (IDUAα) was first validated on MPS1-H patient's fibroblasts which were used to generate the MPS1-H iPSCs line described in our previous work by Lito et al, [30]. The UBI-IDUA-PGK-BSD lentivector allowed a constitutive expression of α-L-iduronidase enzyme (IDUAα) since IDUA is upon ubiquitin (UBI) promotor.…”

Section: Restoration Of Iduaα Activity Of Mps1-h Cells Infected With Ubi-idua-pgk-bsd Lentivectormentioning

confidence: 99%

“…In order to minimize any variation resulting from different genetic background between iPSCs control lines, we generated an isogenic control line by rescuing the functionality of α-L-iduronidase enzyme (IDUAα) in three clones of MPS1-H iPSCs (S1, S2 and S4). The generated rMPS1-H iPSCs clones (S1R, S2R and S4R), resulting from the blasticidin selection of MPS1-H iPSCs transduced with UBI-IDUA-PGK-BSD lentivector were characterized similarly to MPS1-H iPSCs (S4) [30]. Briefly, rMPS1-H iPSCs presented all specificities of pluripotent stem cells.…”

Section: Characterization Of Rescue Rmps1-h Ipscsmentioning

confidence: 99%

“…In this study, we took advantage of the potential of induced pluripotent stem cells (iPSC), derived from a MPS1-H child [30], to reproduce, in vitro, the different steps observed during neural development and to identify any cellular and molecular defects responsible of neuropathological manifestation. To counteract the major cause of transcriptional variation resulting from the genetic background difference between individual lines [31], we generated an isogenic control iPSC line, constitutively expressing the alpha-l-iduronidase.…”

Section: Introductionmentioning

confidence: 99%

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Induced Pluripotent Stem Cells to Understand Mucopolysaccharidosis. I: Demonstration of a Migration Defect in Neural Precursors

Lito

Sidibé

Ilmjärv

et al. 2020

Cells

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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.

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Section: Establishment and Characterization Of Mps1-h Ipsc Linementioning

confidence: 99%

Section: Establishment and Characterization Of Mps1-h Ipsc Linementioning

confidence: 99%

Section: Restoration Of Iduaα Activity Of Mps1-h Cells Infected With Ubi-idua-pgk-bsd Lentivectormentioning

confidence: 99%

Section: Characterization Of Rescue Rmps1-h Ipscsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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