@article{96ac35d44b014e17a01e708cf73b3071,
title = "Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome",
abstract = "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.",
author = "Xonia Carvajal-Vergara and Ana Sevilla and Dsouza, {Sunita L.} and Ang, {Yen Sin} and Christoph Schaniel and Lee, {Dung Fang} and Lei Yang and Kaplan, {Aaron D.} and Adler, {Eric D.} and Roye Rozov and Yongchao Ge and Ninette Cohen and Edelmann, {Lisa J.} and Betty Chang and Avinash Waghray and Jie Su and Sherly Pardo and Lichtenbelt, {Klaske D.} and Marco Tartaglia and Gelb, {Bruce D.} and Lemischka, {Ihor R.}",
note = "Funding Information: Acknowledgements We thank T. James, X. Niu and D. York for their technical support and laboratory management, and B. MacArthur for support in microarray analysis. We also would like to thank K. Moore and her laboratory, and S. Mulero-Navarro from B.D.G.{\textquoteright}s laboratory for their help, and V. Fuster and A. Bernad for their support. This research was funded by grants from the National Institutes of Health (NIH) to I.R.L (5R01GM078465), the Empire State Stem Cell Fund through New York State Department of Health (NYSTEM) C024410 to I.R.L. and C.S., C024176 (HESC-SRF) to I.R.L. and S.L.D., C024407 to B.D.G., American College of Cardiology/Pfizer Research Fellowship to E.D.A., and ERA-Net for research programmes on rare diseases 2009 to M.T. X.C.-V. is a recipient of a Postdoctoral Fellowship from the Ministerio de Ciencia e Innovacion/Instituto de Salud Carlos III, D.-F.L. is a New York Stem Cell Foundation Stanley and Fiona Druckenmiller Fellow and S.P. is a recipient of a Ruth L. Kirschstein National Research Service Award (NRSA) Institutional Research Training Grant (T32).",
year = "2010",
month = jun,
day = "10",
doi = "10.1038/nature09005",
language = "English",
volume = "465",
pages = "808--812",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Research",
number = "7299",
}