Pedigree analysis of one familial hypertrophic cardiomyopathy caused by rare homozygous mutation of TNNI3(p. Arg79Cys) and bioinformatics analysis of the mutation
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摘要: 目的 对TNNI3基因p.Arg79Cys罕见纯合突变导致一家族性肥厚型心肌病进行家系分析，并对突变位点进行生物信息学分析。方法 对先证者及其亲属进行临床资料的评估，采集先证者及其亲属静脉血提取全基因组DNA并进行二代测序，寻找致病基因并进行Sanger测序验证。对致病基因突变进行生物信息学分析，获取突变基因野生型及突变型氨基酸序列，利用计算机对野生型及突变型蛋白质进行二级结构及三级结构预测分析。结果 先证者直系亲属均不符合肥厚型心肌病诊断标准。先证者TNNI3基因5号外显子p.Arg79Cys的纯合突变，先证者母亲、其中1个姐姐及儿子携带TNNI3基因杂合突变，另外1个姐姐未携带TNNI3基因突变。生物信息学分析提示该变异所致的氨基酸改变可能会对蛋白功能产生影响，并且导致蛋白质稳定性降低，在脊椎动物中保守性较好。二级结构预测突变的TNNI3及野生型TNNI3蛋白质二级结构未见明显变化。三级结构预测蛋白三级结构转角处折叠的角度发生了变化，导致蛋白的空间结构发生了变化。结论 TNNI3基因p.Arg79Cys纯合突变可能通过不同于经典单基因遗传的其他遗传模式导致肥厚型心肌病，该位置的突变对蛋白质的结构产生了影响。Abstract: Objective The study aims to perform pedigree analysisof one familial hypertrophic cardiomyopathy(HCM) caused by a rare homozygous mutation ofTNNI3, as well as carry out bioinformatics analysis of the mutation.Methods The clinical data of the proband and his relatives were evaluated. Venous blood was collected from the proband and his family. The whole genome DNA was extracted and screened by targeted next-generation sequencing, following validation by Sanger sequencing. Bioinformatics analysis of the mutation site was carried out. The amino acid sequences of wild-type and mutantTNNI3 were obtained, and the secondary and tertiary structures of the proteins were predicted and analyzed by a computer.Results None of the proband's family members met the diagnostic criteria of HCM. A homozygous mutation ofTNNI3 P. Arg79Cys was found in the proband. The proband's mother, one sister and son carried the heterozygous mutation of the same site while the other sister did not carry the mutation. Sequence alignment showed the residue homology in closely related mammals. Bioinformatics analysis indicated that the changes of the amino acid caused by this mutation might affect the protein function. In addition, the stability of mutant protein was decreased. There was no significant change in the secondary structure between the wild-type TNNI3 and the mutant protein. It was predicted that the angle at the corner of the tertiary structure changed, resulting in the change of the spatial structure of the protein.Conclusion The homozygous mutation ofTNNI3 P. arg79cys may lead to hypertrophic cardiomyopathy through other genetic modes different from the classical single gene inheritance. The mutation at this site has an impact on the structure of the protein.
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Key words:
- hypertrophic cardiomyopathy /
- TNNI3 /
- homozygous mutation /
- protein structure
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图 4 TNNI3突变位点在脊柱动物中的氨基酸同源性
Figure 4. Sequence homology analysis of amino acid of TNNI3 in vertebrates
图 5 野生型(TNNI3-W)及突变型(TNNI3-M)TNNI3蛋白二级结构预测结果
Figure 5. The prediction results of protein secondary structure by Geneious Pro software
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