Patient-specific induced pluripotent stem cell derived models of LEOPARD syndrome

By Xonia Carvajal-Vergara, A. Sevilla, S. D'Souza, Yen-Sin Ang, C. Schaniel, Dung‐Fang Lee, Lei Yang, A. Kaplan, Eric D. Adler, Roye Rozov and 11 more. Nature, 2010

728 citations recorded by the source corpus.

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.

View Paper: https://www.semanticscholar.org/paper/fb176b6504e797fcff1571abf9ea83d8ff66785f

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Citations in the corpus

• Production of De Novo Cardiomyocytes: Human Pluripotent Stem Cell Differentiation and Direct Reprogramming (2012, unknown): “Studies to date have largely concentrated on recapitulating genetic disease phenotypes in vitro, such as long QT syndromes (Itzhaki et al., 2011a; Matsa et al., 2011; Moretti et al., 2010), Timothy syndrome (Yazawa et al., 2011), and LEOPARD syndrome (Carvajal-Vergara et al., 2010).”
• Abnormal Calcium Handling Properties Underlie Familial Hypertrophic Cardiomyopathy Pathology in Patient-Specific Induced Pluripotent Stem Cells (2013, background): “…and has previously been used to model several hereditary cardiovascular disorders in vitro including dilated cardiomyopathy, LEOPARD, and long QT syndrome (Carvajal-Vergara et al., 2010; Itzhaki et al., 2011; Moretti et al., 2010; Narsinh et al., 2011a; Sun et al., 2012; Yazawa et al., 2011).”
• High purity human-induced pluripotent stem cell-derived cardiomyocytes: electrophysiological properties of action potentials and ionic currents. (2011, background): “HUMAN-INDUCED PLURIPOTENT stem cell (hiPSC)-derived cardiomyocytes are providing new approaches to studying the cardiac cellular properties of healthy individuals and those with inheritable diseases (5, 16, 29, 49, 52).”
• Somatic cell reprogramming and transitions between pluripotent states: facts, hypotheses, unresolved issues (2010, unknown): “This is important because for some iPSCs derived from patients, a disease-specific in vitro phenotype has been reported (Carvajal-Vergara et al., 2010; Ebert et al., 2009).”