A Double Heterozygous Mutation of TNNI3 Causes Hypertrophic Cardiomyopathy in a Han Chinese Family.
OBJECTIVE
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.
Department of Cardiovascular Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Hua
H
Zheng
Huajie
H
Huang
Zhisong
Z
Ji
Qi
Q
Yang
Qiuxia
Q
Yu
Fan
F
Shen
Cuixian
C
Liu
Fu
F
Xiong
D000328:Adult; D015153:Blotting, Western; D002312:Cardiomyopathy, Hypertrophic / Q000097:blood / Q000235:genetics*; D002681:China; D017931:DNA Primers; D004452:Echocardiography; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017422:Sequence Analysis, DNA; D055815:Young Adult
D017931:DNA Primers