先天性心脏病患者TGFB1基因变异的鉴定和表征

IF 0.8 Q4 GENETICS & HEREDITY Meta Gene Pub Date : 2022-02-01 DOI:10.1016/j.mgene.2021.100987
Manohar Lal Yadav , Ashutosh Narayan Bhasker , Ashok Kumar , Bhagyalaxmi Mohapatra
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引用次数: 2

摘要

研究背景先天性心脏病(CHDs)被认为是由胚胎心脏发育过程中基因功能异常引起的。已知转化生长因子- β 1 (TGFB1)在早期胚胎心脏中表达并调节心脏发育。方法采用Sanger测序法对238例冠心病患者TGFB1编码区进行筛选。通过病例-对照关联研究确定冠心病的危险等位基因。采用硅和体外方法在P19细胞系中阐明TGFB1罕见错义变体的作用。结果鉴定出一种罕见的错义变异(c.29C >G;p.P10R)在2例TGFB1信号肽中的表达(MAF = 0.0042017),而在200例健康对照中不存在。虽然这种变异在gnomAD (rs1800470, MAF =0.0002386)和ExAC数据库(MAF = 0.00064)中有报道,但在INDEX-db和GenomeAsia 100K数据库中没有报道。我们还发现了三个多态性,即c.29C >T;p.P10L, c.74G >C;p.R25P和c.788C >T;p.T263I。病例对照研究显示,c.29C >T (rs1800470)变异是一个危险因素,与冠心病表型显著相关(OR = 1.4361, P = 0.0083)。然而,c.74G >C (rs1800471)和C . 788c >T (rs1800472)等位基因与该病无关。此外,两个罕见的同义变体,即c.348C >T;p.T116T (MAF = 0.0042017)和c.501C >T;p.H167H (MAF = 0.00210084)也分别在2例和1例中被鉴定出来。这些在200个对照组中都不存在。芯片分析显示错义变异p.P10R增强了信号肽α-螺旋的形成,可能增加了TGFB1的分泌。荧光素酶报告试验显示,p(SBE)4 (p = 0.016)和p(CAGA)12 (p = 0.0004)启动子的活性在p.P10R突变体与野生型TGFB1的反应中显著增加。结论TGFB1的p.P10R变体具有潜在的功能获得活性,而c.29C >T变异是与冠心病相关的危险因素。
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Identification and characterization of genetic variants of TGFB1 in patients with congenital heart disease

Background

Congenital heart diseases (CHDs) are believed to be caused by abnormal gene functioning during embryonic heart development. Transforming growth factor-beta1 (TGFB1) is known to express in the early embryonic heart and regulates heart development.

Methods

In this study, the coding region of TGFB1 was screened for 238 CHD patients by Sanger sequencing. Case-control association study was performed to identify the risk allele for CHD. In silico and in vitro approaches were used to elucidate the role of rare missense variant of TGFB1 using P19 cell line.

Results

We identified a rare missense variant (c.29C > G; p.P10R) in the signal peptide of the TGFB1 in two cases (MAF = 0.0042017), which was absent in 200 healthy controls. Although this variation is reported in the gnomAD (rs1800470, MAF =0.0002386) and the ExAC database (MAF = 0.00064), it is not reported in INDEX-db and GenomeAsia 100K databases. We also found three polymorphisms, namely c.29C > T; p.P10L, c.74G > C; p.R25P and c.788C > T; p.T263I. Case-control studies revealed that c.29C > T (rs1800470) variation is a risk factor, significantly associated with the CHD phenotype (OR = 1.4361, P = 0.0083). However, c.74G > C (rs1800471) and c.788C > T (rs1800472) alleles are not associated with the disease. Additionally, two rare synonymous variations, i.e. c.348C > T; p.T116T (MAF = 0.0042017) and c.501C > T; p.H167H (MAF = 0.00210084) were also identified in two and one cases, respectively. These were absent in the 200 controls. In silico analysis showed that missense variation p.P10R enhances the formation of the α-helix in the signal peptide, which possibly increases the TGFB1 secretion. The luciferase-reporter assay demonstrated significantly increased activity of p(SBE)4 (P = 0.016) and p(CAGA)12 (P = 0.0004) promoters in response to p.P10R mutant versus wild-type TGFB1.

Conclusion

The p.P10R variant of TGFB1 implicated a gain-of-function activity which is potentially deleterious, while the c.29C > T variation is a risk factor associated with the CHD.

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来源期刊
Meta Gene
Meta Gene Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
1.10
自引率
0.00%
发文量
20
期刊介绍: Meta Gene publishes meta-analysis, polymorphism and population study papers that are relevant to both human and non-human species. Examples include but are not limited to: (Relevant to human specimens): 1Meta-Analysis Papers - statistical reviews of the published literature of human genetic variation (typically linked to medical conditionals and/or congenital diseases) 2Genome Wide Association Studies (GWAS) - examination of large patient cohorts to identify common genetic factors that influence health and disease 3Human Genetics Papers - original studies describing new data on genetic variation in smaller patient populations 4Genetic Case Reports - short communications describing novel and in formative genetic mutations or chromosomal aberrations (e.g., probands) in very small demographic groups (e.g., family or unique ethnic group). (Relevant to non-human specimens): 1Small Genome Papers - Analysis of genetic variation in organelle genomes (e.g., mitochondrial DNA) 2Microbiota Papers - Analysis of microbiological variation through analysis of DNA sequencing in different biological environments 3Ecological Diversity Papers - Geographical distribution of genetic diversity of zoological or botanical species.
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