| Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome. | |
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MedLine Citation:
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PMID: 20535210 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The generation of reprogrammed induced pluripotent stem cells (iPSCs) from patients with defined genetic disorders holds the promise of increased understanding of the aetiologies of complex diseases and may also facilitate the development of novel therapeutic interventions. We have generated iPSCs from patients with LEOPARD syndrome (an acronym formed from its main features; that is, lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonary valve stenosis, abnormal genitalia, retardation of growth and deafness), an autosomal-dominant developmental disorder belonging to a relatively prevalent class of inherited RAS-mitogen-activated protein kinase signalling diseases, which also includes Noonan syndrome, with pleomorphic effects on several tissues and organ systems. The patient-derived cells have a mutation in the PTPN11 gene, which encodes the SHP2 phosphatase. The iPSCs have been extensively characterized and produce multiple differentiated cell lineages. A major disease phenotype in patients with LEOPARD syndrome is hypertrophic cardiomyopathy. We show that in vitro-derived cardiomyocytes from LEOPARD syndrome iPSCs are larger, have a higher degree of sarcomeric organization and preferential localization of NFATC4 in the nucleus when compared with cardiomyocytes derived from human embryonic stem cells or wild-type iPSCs derived from a healthy brother of one of the LEOPARD syndrome patients. These features correlate with a potential hypertrophic state. We also provide molecular insights into signalling pathways that may promote the disease phenotype. |
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Authors:
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Xonia Carvajal-Vergara; Ana Sevilla; Sunita L D'Souza; Yen-Sin Ang; Christoph Schaniel; Dung-Fang Lee; Lei Yang; Aaron D Kaplan; Eric D Adler; Roye Rozov; Yongchao Ge; Ninette Cohen; Lisa J Edelmann; Betty Chang; Avinash Waghray; Jie Su; Sherly Pardo; Klaske D Lichtenbelt; Marco Tartaglia; Bruce D Gelb; Ihor R Lemischka |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Nature Volume: 465 ISSN: 1476-4687 ISO Abbreviation: Nature Publication Date: 2010 Jun |
Date Detail:
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Created Date: 2010-06-10 Completed Date: 2010-07-22 Revised Date: 2010-12-17 |
Medline Journal Info:
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Nlm Unique ID: 0410462 Medline TA: Nature Country: England |
Other Details:
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Languages: eng Pagination: 808-12 Citation Subset: IM |
Affiliation:
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Department of Gene and Cell Medicine, Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, New York 10029, USA. xcarvajal@gmail.com |
| Data Bank Information | |
Bank Name/Acc. No.:
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GEO/GSE20473 |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adult Cell Differentiation Cell Line Cell Lineage Cells, Cultured Embryonic Stem Cells / metabolism Enzyme Activation Female Fibroblasts / metabolism, pathology Gene Expression Profiling Homeodomain Proteins / genetics Humans Individualized Medicine* Induced Pluripotent Stem Cells / enzymology, metabolism, pathology* LEOPARD Syndrome / drug therapy, metabolism, pathology* Male Mitogen-Activated Protein Kinases / metabolism Models, Biological* Myocytes, Cardiac / metabolism, pathology NFATC Transcription Factors / genetics, metabolism Octamer Transcription Factor-3 / genetics Phosphoproteins / analysis Polymerase Chain Reaction Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics, metabolism SOXB1 Transcription Factors / genetics |
| Grant Support | |
ID/Acronym/Agency:
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5R01GM078465/GM/NIGMS NIH HHS; R01 GM078465-03/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Homeodomain Proteins; 0/NANOG protein, human; 0/NFATC Transcription Factors; 0/NFATC4 protein, human; 0/Octamer Transcription Factor-3; 0/POU5F1 protein, human; 0/Phosphoproteins; 0/SOX2 protein, human; 0/SOXB1 Transcription Factors; EC 2.7.11.24/Mitogen-Activated Protein Kinases; EC 3.1.3.48/PTPN11 protein, human; EC 3.1.3.48/Protein Tyrosine Phosphatase, Non-Receptor Type 11 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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