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Article Abstract
Aims: Perform analysis of human mutations to elucidate their pathogenic role in Noonan syndrome (NS).
Background: NS is an autosomal dominant genetic disorder caused by single nucleotide mutation in PTPN11, , RAF1, and KRAS genes. NS is thought to affect approximately 1 in 1000. NS patients suffer different pathogenic effects depending on the mutations they carry. Analysis of the mutations would be a promising predictor in identifying the pathogenic effect of NS.
Methods: We performed computational analysis of the gene to identify the pathogenic nonsynonymous single nucleotide polymorphisms (nsSNPs) th a t cause NS. variants were retrieved from the SNP database (dbSNP) and analyzed by tools I-Mutant, iPTREESTAB, and MutPred to elucidate their structural and functional characteristics.
Results: We found that 11 nsSNPs of that were linked to NS. 3D modeling of the wild-type and the 11 nsSNPs of showed that interacts with cardiac proteins GATA4, TNNT2, and ACTN2. We also found that GRB2 and HRAS act as intermediate molecules between and cardiac proteins. Our analysis findings were further validated using induced cardiomyocytes (iCMCs) derived from NS patients carrying gene variant c.1654A>G (NSiCMCs) and compared to control human skin fibroblast-derived iCMCs (C-iCMCs). Our data confirmed that the , GRB2 and HRAS gene expressions as well as the activated ERK protein, were significantly decreased in NS-iCMCs when compared to C-iCMCs.
Conclusion: This is the first and study demonstrating that 11 nsSNPs of play deleterious pathogenic roles in causing NS.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8905634 | PMC |
| http://dx.doi.org/10.2174/1389202922666211130144221 | DOI Listing |
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