A Double Heterozygous Mutation of <b><i>TNNI3</i></b> Causes Hypertrophic Cardiomyopathy in a Han Chinese Family

Abstract

Objectives: To investigate the variations in the TNNI3 gene in a Chinese Han family affected by hypertrophic cardiomyopathy (HCM) and the potential molecular mechanism linking these mutations with disease. Methods: Peripheral venous blood was acquired from family members, and TNNI3 mutations were identified by DNA sequencing. The pathophysiology of TNNI3 mutations was investigated using bioinformatics, subcellular localization determination and Western blotting. Results: Sanger sequencing revealed that the proband possessed 2 heterozygous mutations, c.235C>T and c.470C>T, located at exons 4 and 6 of the TNNI3 gene. The proband (II-2) and her brother (II-1), who had been previously diagnosed with HCM, harbored both mutations whereas their healthy parents harbored only 1. Alignment of the TNNI3 amino acid sequence indicated that the two Pro residues were highly conserved across species. Subcellular localization showed that both wild-type (WT) and mutant TNNI3 proteins were localized at the cell nucleus. Western blot analysis of expression in human embryonic kidney 293T cells showed that the intracellular levels of the mutant proteins were significantly decreased compared to WT TNNI3 (p < 0.01). Conclusions: Our findings showed that a double heterozygous mutation in the TNNI3 gene is involved in the pathogenesis of HCM via haploinsufficiency. These results will inspire further studies to investigating the link between the TNNI3 gene and HCM.

Potential digenic inheritance of familial hypertrophic cardiomyopathy identified by whole‐exome sequencing

“…This may result in a more severe clinical phenotype with a higher incidence of heart failure or sudden death (Ingles 2 of 6 | REN Et al. et al, 2005;Maron, Maron, & Semsarian, 2012;Zheng et al, 2016). Recently, the oligogenic inheritance of congenital heart disease has been proved by the experimental model (Gifford et al, 2019).…”

“…Most HCM patients are found to carry one pathogenic allele; however, a minority harbor more than one variant in one gene or two/three distinct genes. This may result in a more severe clinical phenotype with a higher incidence of heart failure or sudden death (Ingles et al, ; Maron, Maron, & Semsarian, ; Zheng et al, ). Recently, the oligogenic inheritance of congenital heart disease has been proved by the experimental model (Gifford et al, ).…”

Myosin inhibitor reverses hypertrophic cardiomyopathy in pediatric iPSC-cardiomyocytes to mirror variant correction

“…32 33 as well as in an individual with dilated cardiomyopathy, 34 and has been reported to cause a decrease in TNNI3 protein level (similar to our patient), but its effect on CM function has not been previously studied. 35 Overall, our findings suggest that even in patients with HCM caused by sarcomere gene variants, the pathophysiologic mechanisms that contribute to the disease phenotype likely differ. This could have implications for the response to different pharmacological agents.…”

Myosin inhibitor reverses hypertrophic cardiomyopathy in genotypically diverse pediatric iPSC-cardiomyocytes to mirror variant correction

“… 32 TNNI3 A157V has been reported in over 20 individuals with HCM, 33 as well as in an individual with dilated cardiomyopathy, 34 and has been reported to cause a decrease in TNNI3 protein level (similar to our patient), but its effect on CM function has not been previously studied. 35 …”