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.

journal_name

Nature

journal_title

Nature

authors

Carvajal-Vergara X,Sevilla A,D'Souza SL,Ang YS,Schaniel C,Lee DF,Yang L,Kaplan AD,Adler ED,Rozov R,Ge Y,Cohen N,Edelmann LJ,Chang B,Waghray A,Su J,Pardo S,Lichtenbelt KD,Tartaglia M,Gelb BD,Lemischka IR

doi

10.1038/nature09005

subject

Has Abstract

pub_date

2010-06-10 00:00:00

pages

808-12

issue

7299

eissn

0028-0836

issn

1476-4687

pii

nature09005

journal_volume

465

pub_type

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