Noonan syndrome patient-specific induced cardiomyocyte model carrying SOS1 gene variant c.1654A > G.
Document Type
Article
Publication Date
3-1-2021
Identifier
DOI: 10.1016/j.yexcr.2021.112508
Abstract
Noonan syndrome (NS) is a dominant autosomal genetic disorder, associated with mutations in several genes that exhibit multisystem abnormal development including cardiac defects. NS associated with the Son of Sevenless homolog 1 (SOS1) gene mutation attributes to the development of cardiomyopathy and congenital heart defects. Since the treatment option for NS is very limited, an in vitro disease model with SOS1 gene mutation would be beneficial for exploring therapeutic possibilities for NS. We reprogrammed cardiac fibroblasts obtained from a NS patient and normal control skin fibroblasts (C-SF) into induced pluripotent stem cells (iPSCs). We identified NS-iPSCs carry a heterozygous single nucleotide variation in the SOS1 gene at the c.1654A > G. Furthermore, the control and NS-iPSCs were differentiated into induced cardiomyocytes (iCMCs), and the electron microscopic analysis showed that the sarcomeres of the NS-iCMCs were highly disorganized. FACS analysis showed that 47.5% of the NS-iCMCs co-expressed GATA4 and cardiac troponin T proteins, and the mRNA expression levels of many cardiac related genes, studied by qRT-PCR array, were significantly reduced when compared to the control C-iCMCs. We report for the first time that NS-iPSCs carry a single nucleotide variation in the SOS1 gene at the c.1654A > G were showing significantly reduced cardiac genes and proteins expression as well as structurally and functionally compromised when compared to C-iCMCs. These iPSCs and iCMCs can be used as a modeling platform to unravel the pathologic mechanisms and also the development of novel drug for the cardiomyopathy in patients with NS.
Journal Title
Experimental cell research
Volume
400
Issue
1
First Page
112508
Last Page
112508
Keywords
Cardiomyopathy; Induced cardiomyocytes; Induced pluripotent stem cells; Noonan syndrome; SOS1 gene
Recommended Citation
Gurusamy N, Rajasingh S, Sigamani V, et al. Noonan syndrome patient-specific induced cardiomyocyte model carrying SOS1 gene variant c.1654A>G. Exp Cell Res. 2021;400(1):112508. doi:10.1016/j.yexcr.2021.112508
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