Centre for Cellular and Molecular Biology, CSIR, Uppal Road, Hyderabad 500 007, India.
BMC Med Genet. 2012 Aug 10;13:69. doi: 10.1186/1471-2350-13-69.
Troponin I (TNNI3) is the inhibitory subunit of the thin filament regulatory complex Troponin, which confers calcium-sensitivity to striated muscle actomyosin ATPase activity. Mutations (2-7%) in this gene had been reported in hypertrophic cardiomyopathy patients (HCM). However, the frequencies of mutations and associated clinical presentation have not been established in cardiomyopathy patients of Indian origin, hence we have undertaken this study.
We have sequenced all the exons, including the exon-intron boundaries of TNNI3 gene in 101 hypertrophic cardiomyopathy patients (HCM), along with 160 healthy controls, inhabited in the same geographical region of southern India.
Our study revealed a total of 16 mutations. Interestingly, we have observed Arginine to Glutamine (R to Q) mutation at 3 positions 98, 141 and 162, exclusively in HCM patients with family history of sudden cardiac death. The novel R98Q was observed in a severe hypertrophic obstructive cardiomyopathy patient (HOCM). The R141Q mutation was observed in two familial cases of severe asymmetric septal hypertrophy (ASH++). The R162Q mutation was observed in a ASH++ patient with mean septal thickness of 29 mm, and have also consists of allelic heterogeneity by means of having one more synonymous (E179E) mutation at g.4797: G → A: in the same exon 7, which replaces a very frequent codon (GAG: 85%) with a rare codon (GAA: 14%). Screening for R162Q mutation in all the available family members revealed its presence in 9 individuals, including 7 with allelic heterogeneity (R162Q and E179E) of which 4 were severely affected. We also found 2 novel SNPs, (g.2653; G → A and g.4003 C → T) exclusively in HCM, and in silico analysis of these SNPs have predicted to cause defect in recognition/binding sites for proteins responsible for proper splicing.
Our study has provided valuable information regarding the prevalence of TNNI3 mutations in Indian HCM patients and its risk assessment, these will help in genetic counseling and to adopt appropriate treatment strategies.
肌钙蛋白 I（TNNI3）是肌钙蛋白细肌丝调节复合物的抑制亚基，为横纹肌肌球蛋白 ATP 酶的钙敏感性提供了保障。该基因的突变（2-7%）已在肥厚型心肌病患者（HCM）中被报道。然而，在印度裔的心肌病患者中，基因突变的频率及其相关临床表现尚未确定，因此我们进行了这项研究。
我们对 101 名肥厚型心肌病患者（HCM）和 160 名居住在印度南部同一地区的健康对照者的 TNNI3 基因所有外显子及其内含子边界进行了测序。
我们的研究共发现了 16 种突变。有趣的是，我们仅在有家族性心脏性猝死史的 HCM 患者中观察到 3 个位置（98、141 和 162）的精氨酸到谷氨酰胺（R 到 Q）突变。在一名严重肥厚性梗阻性心肌病患者（HOCM）中观察到新的 R98Q。在两名严重非对称性室间隔肥厚症（ASH++）的家族病例中观察到 R141Q 突变。在一名 ASH++患者中观察到 R162Q 突变，该患者的室间隔平均厚度为 29mm，并且在同一外显子 7 中还存在等位基因异质性，即另一个同义突变（E179E）g.4797：G→A：取代了一个非常常见的密码子（GAG：85%）为稀有密码子（GAA：14%）。对所有可获得的家族成员进行 R162Q 突变筛查，发现有 9 人存在该突变，其中 7 人存在等位基因异质性（R162Q 和 E179E），其中 4 人病情严重。我们还发现了 2 个新的 SNP（g.2653；G→A 和 g.4003 C→T），仅在 HCM 中发现，对这些 SNP 的计算机分析预测会导致负责正确剪接的蛋白质识别/结合位点的缺陷。
我们的研究为印度 HCM 患者 TNNI3 突变的流行情况及其风险评估提供了有价值的信息，这将有助于遗传咨询和采取适当的治疗策略。
