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Article: A new patient‐derived iPSC model for dystroglycanopathies validates a compound that increases glycosylation of α‐dystroglycan

TitleA new patient‐derived iPSC model for dystroglycanopathies validates a compound that increases glycosylation of α‐dystroglycan
Authors
KeywordsCRISPR
fukutin-related protein
high-throughput screening
human-induced pluripotent stem cells
α-dystroglycan
Issue Date2019
PublisherWiley-Blackwell Publishing Ltd. The Journal's web site is located at http://www.emboreports.org
Citation
EMBO Reports, 2019, v. 20 n. 11, p. article no. e47967 How to Cite?
AbstractDystroglycan, an extracellular matrix receptor, has essential functions in various tissues. Loss of α‐dystroglycan‐laminin interaction due to defective glycosylation of α‐dystroglycan underlies a group of congenital muscular dystrophies often associated with brain malformations, referred to as dystroglycanopathies. The lack of isogenic human dystroglycanopathy cell models has limited our ability to test potential drugs in a human‐ and neural‐specific context. Here, we generated induced pluripotent stem cells (iPSCs) from a severe dystroglycanopathy patient with homozygous FKRP (fukutin‐related protein gene) mutation. We showed that CRISPR/Cas9‐mediated gene correction of FKRP restored glycosylation of α‐dystroglycan in iPSC‐derived cortical neurons, whereas targeted gene mutation of FKRP in wild‐type cells disrupted this glycosylation. In parallel, we screened 31,954 small molecule compounds using a mouse myoblast line for increased glycosylation of α‐dystroglycan. Using human FKRP‐iPSC‐derived neural cells for hit validation, we demonstrated that compound 4‐(4‐bromophenyl)‐6‐ethylsulfanyl‐2‐oxo‐3,4‐dihydro‐1H‐pyridine‐5‐carbonitrile (4BPPNit) significantly augmented glycosylation of α‐dystroglycan, in part through upregulation of LARGE1 glycosyltransferase gene expression. Together, isogenic human iPSC‐derived cells represent a valuable platform for facilitating dystroglycanopathy drug discovery and therapeutic development.
Persistent Identifierhttp://hdl.handle.net/10722/290840
ISSN
2019 Impact Factor: 7.497
2015 SCImago Journal Rankings: 4.291
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorKim, J-
dc.contributor.authorLana, B-
dc.contributor.authorTorelli, S-
dc.contributor.authorRyan, D-
dc.contributor.authorCatapano, F-
dc.contributor.authorAla, P-
dc.contributor.authorLuft, C-
dc.contributor.authorStevens, E-
dc.contributor.authorKonstantinidis, E-
dc.contributor.authorLouzada, S-
dc.contributor.authorFu, B-
dc.contributor.authorParedes‐Redondo, A-
dc.contributor.authorChan, AWE-
dc.contributor.authorYang, F-
dc.contributor.authorStemple, DL-
dc.contributor.authorLiu, P-
dc.contributor.authorKetteler, R-
dc.contributor.authorSelwood, DL-
dc.contributor.authorMuntoni, F-
dc.contributor.authorLin, YY-
dc.date.accessioned2020-11-02T05:47:51Z-
dc.date.available2020-11-02T05:47:51Z-
dc.date.issued2019-
dc.identifier.citationEMBO Reports, 2019, v. 20 n. 11, p. article no. e47967-
dc.identifier.issn1469-221X-
dc.identifier.urihttp://hdl.handle.net/10722/290840-
dc.description.abstractDystroglycan, an extracellular matrix receptor, has essential functions in various tissues. Loss of α‐dystroglycan‐laminin interaction due to defective glycosylation of α‐dystroglycan underlies a group of congenital muscular dystrophies often associated with brain malformations, referred to as dystroglycanopathies. The lack of isogenic human dystroglycanopathy cell models has limited our ability to test potential drugs in a human‐ and neural‐specific context. Here, we generated induced pluripotent stem cells (iPSCs) from a severe dystroglycanopathy patient with homozygous FKRP (fukutin‐related protein gene) mutation. We showed that CRISPR/Cas9‐mediated gene correction of FKRP restored glycosylation of α‐dystroglycan in iPSC‐derived cortical neurons, whereas targeted gene mutation of FKRP in wild‐type cells disrupted this glycosylation. In parallel, we screened 31,954 small molecule compounds using a mouse myoblast line for increased glycosylation of α‐dystroglycan. Using human FKRP‐iPSC‐derived neural cells for hit validation, we demonstrated that compound 4‐(4‐bromophenyl)‐6‐ethylsulfanyl‐2‐oxo‐3,4‐dihydro‐1H‐pyridine‐5‐carbonitrile (4BPPNit) significantly augmented glycosylation of α‐dystroglycan, in part through upregulation of LARGE1 glycosyltransferase gene expression. Together, isogenic human iPSC‐derived cells represent a valuable platform for facilitating dystroglycanopathy drug discovery and therapeutic development.-
dc.languageeng-
dc.publisherWiley-Blackwell Publishing Ltd. The Journal's web site is located at http://www.emboreports.org-
dc.relation.ispartofEMBO Reports-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectCRISPR-
dc.subjectfukutin-related protein-
dc.subjecthigh-throughput screening-
dc.subjecthuman-induced pluripotent stem cells-
dc.subjectα-dystroglycan-
dc.titleA new patient‐derived iPSC model for dystroglycanopathies validates a compound that increases glycosylation of α‐dystroglycan-
dc.typeArticle-
dc.identifier.emailLiu, P: pliu88@hku.hk-
dc.identifier.authorityLiu, P=rp02328-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.15252/embr.201947967-
dc.identifier.pmid31566294-
dc.identifier.pmcidPMC6832011-
dc.identifier.scopuseid_2-s2.0-85073944488-
dc.identifier.hkuros317872-
dc.identifier.volume20-
dc.identifier.issue11-
dc.identifier.spagearticle no. e47967-
dc.identifier.epagearticle no. e47967-
dc.publisher.placeUnited Kingdom-

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