Background: JAG1 is an evolutionarily conserved ligand for Notch receptor and functions in the cell fate decisions, cell-cell interactions throughout the development of heart especially right heart development. Tetralogy of Fallot (TOF) is essentially a right sided heart disease with characteristic features of ventricular septal defect, right ventricular outflow tract obstruction, aortic dextroposition and right ventricular hypertrophy. Hence, the present study was investigated to identify mutations of JAG1 gene in an Indian cohort of patients with TOF.
Methods: The clinical data and blood samples from 84 unrelated subjects with TOF were collected and evaluated in comparison with 87 healthy individuals. PCR based single strand conformation polymorphism analysis and subsequent bidirectional DNA sequencing of conformers was carried in the exon 6 of JAG1 gene.
Results: The DNA sequences aligned with NCBI-BLAST led to the identification of four novel variations including one nonsense 765 C>A, two missense 814 G>T, 834 G>T; and one silent alteration 816 G>T in TOF patients. The protein structure of JAG1 predicts that these variations effect first and second epidermal growth factor like repeat and might disturb ligand-receptor binding ability. The presence of similar variations was not observed in healthy controls. The software CLUSTAL-W showed the inter species conservation of altered amino acids in missense mutations.
Conclusion: Disease-associating novel JAG1 gene variations were found in TOF patients, and seem to play an important role in the causation of the disease.
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