Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome.
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.
Carvajal-Vergara
Xonia
X
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
Sevilla
Ana
A
D'Souza
Sunita L
SL
Ang
Yen-Sin
YS
Schaniel
Christoph
C
Lee
Dung-Fang
DF
Yang
Lei
L
Kaplan
Aaron D
AD
Adler
Eric D
ED
Rozov
Roye
R
Ge
Yongchao
Y
Cohen
Ninette
N
Edelmann
Lisa J
LJ
Chang
Betty
B
Waghray
Avinash
A
Su
Jie
J
Pardo
Sherly
S
Lichtenbelt
Klaske D
KD
Tartaglia
Marco
M
Gelb
Bruce D
BD
Lemischka
Ihor R
IR
D000328:Adult; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D044542:LEOPARD Syndrome / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000235:genetics; D010750:Phosphoproteins / Q000032:analysis; D016133:Polymerase Chain Reaction; D057285:Precision Medicine; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics
D018398:Homeodomain Proteins; C486780:NANOG protein, human; D050778:NFATC Transcription Factors; C494010:NFATC4 protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D010750:Phosphoproteins; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D020928:Mitogen-Activated Protein Kinases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11