Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome
Open accessAbstract
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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The capacity of iPSCs for scalable production of diverse cell types benefits researchers by reducing obstacles with procedures such as apheresis.
“The capacity of iPSCs for the scalable production of diverse cell types benefits researchers by reducing obstacles with procedures such as apheresis, which involves separating specific components from the blood and retuning the remaining components to the donor’s circulation, whilst obtaining human cells [3].”
From Utility of iPSC-Derived Cells for Disease Modeling, Drug Development, and Cell Therapy (2022) · cites this paper as [3]
The paper reports that patient-derived iPSCs differentiated into multiple cell types and describes iPSC-derived cells as a resource for studying disease (Abstract; page unavailable). It does not establish scalable production or say that iPSCs reduce obstacles associated with apheresis; its patient cells were obtained from skin biopsies (Methods Summary, Cell culture; page unavailable). (LLM, conf=0.84)
Experimental — accuracy not yet measuredAn extensive list of cardiovascular models has been generated from patient-derived iPSCs, including long QT syndrome, hypertrophic cardiomyopathy, Leopard syndrome, and arrhythmogenic right ventricular cardiomyopathy/dysplasia.
“To date, there has been an extensive list of cardiovascular models generated from patient-derived iPSCs such as long QT syndrome (LQTS), hypertrophic cardiomyopathy, Leopard syndrome, and arrhythmogenic right ventricular cardiomyopathy/dysplasia [1,2,3,4].”
From Utility of iPSC-Derived Cells for Disease Modeling, Drug Development, and Cell Therapy (2022) · cites this paper as [3]
Patient-specific genotype can significantly affect disease onset and progression and influence drug responses.
“It is known that patient-specific genotype can significantly affect disease onset and progression, as well as influence drug responses [211,214,410].”
From Cardiovascular disease models: A game changing paradigm in drug discovery and screening (2019) · cites this paper as [214]
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- Authors
- Carvajal-Vergara, X., Sevilla, A., D’Souza, S. L., Ang, Y.-S., Schaniel, C., Lee, D.-F., Yang, L., Kaplan, A. D., Adler, E. D., Rozov, R., Ge, Y., Cohen, N., Edelmann, L. J., Chang, B., Waghray, A., Su, J., Pardo, S., Lichtenbelt, K. D., Tartaglia, M., Gelb, B. D., & Lemischka, I. R.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Mount Sinai Hospital (US)
- University Medical Center Utrecht (NL)
- Istituto Superiore di Sanità (IT)
- Corresponding author
- Lemischka, Ihor R.
- ORCID
- Venue
- Nature
- Published
- 2010-06
- Volume
- 465
- Issue
- 7299
- Pages
- 808-812
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2885001
- OpenAlex
- W2143747124
- Cited by
- 690
- References
- 31
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 24 · 2023: 15 · 2022: 24 · 2021: 32 · 2020: 32 · 2019: 32 · 2018: 31 · 2017: 30 · 2016: 42 · 2015: 76 · 2014: 56 · 2013: 82 · 2012: 97
- FWCI
- 37.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM078465)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- LEOPARD syndrome, induced pluripotent stem cells, cardiomyocytes, cardiac hypertrophy, hypertrophic cardiomyopathy, PTPN11 mutation, SHP2, RAS/MAPK pathway, Noonan syndrome, sarcomeric organization, iPSC differentiation protocols, disease modeling, therapeutic drug screening
- MeSH terms
- Nanog Homeobox Protein, Adult, Cell Differentiation, Cell Line, Cells, Cultured, Enzyme Activation, Female, Fibroblasts, Humans, Male, Models, Biological, Phosphoproteins, Polymerase Chain Reaction, Homeodomain Proteins, Cell Lineage, Gene Expression Profiling, Mitogen-Activated Protein Kinases, Myocytes, Cardiac, LEOPARD Syndrome, NFATC Transcription Factors, Octamer Transcription Factor-3, Embryonic Stem Cells, Protein Tyrosine Phosphatase, Non-Receptor Type 11, SOXB1 Transcription Factors, Induced Pluripotent Stem Cells, Precision Medicine
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