Decreased activity of RCAN1.4 is a potential risk factor for congenital heart disease in a Han Chinese population
Decreased activity of RCAN1.4 is a potential risk factor for congenital heart disease in a Han Chinese population
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DOI：
10.1007/s13238-018-0525-8
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发表时间：
2018
期刊：
影响因子：
21.1
通讯作者：
Hongyan Wang
中科院分区：
文献类型：
--
作者：
Liangping Cheng;Peiqiang Li;He Wang;Xueyan Yang;Huiming Zhou;Wufan Tao;Jie Tian;Hongyan Wang
Congenital heart disease (CHD) is the leading cause of birth defect-related deaths and affects approximately 1 per 100 live births. However, the aetiology of CHD remains unclear. The RCAN1 gene is a regulatory protein of calcineurin/NFATc signalling pathway which is essential for heart development. However, whether RCAN1 is involved in developing human CHD has remained elusive. We performed an association study of RCAN1 variants with CHD by sequencing blood samples from 870 patients and 1320 controls in a Han Chinese population. The results revealed that a SNP (rs2243890 A>G) in the promoter region of RCAN1.4 transcripts (one of RCAN1 transcripts) was significantly associated with CHD. Individuals carrying the G allele had a 1.62-fold increased risk of developing CHD compared with those carrying the A allele (odds ratio, 1.62; 95% confidence interval, 1.29-2.03; p=4.68e-05). Quantitative real-time PCR of human heart tissues revealed that rs2243890 A>G markedly down-regulated RCAN1.4 mRNA levels in vivo. This result was further validated by our luciferase reporter assay showing that the minor G allele decreased RCAN1.4 promoter activity in vitro. Our electrophoretic mobility shift assay indicated that the rs2243890 G allele has a higher binding affinity for some nuclear proteins. In addition, we identified a rare functional mutation, p.E25K, in RCAN1.4 in a VSD patient and demonstrated that RCAN1.4E25K is a loss-of-function mutation in zebrafish model as well as in an in vitro luciferase reporter assay with transfected 293T cells. Our results indicate that RCAN1.4 deficiency potentially increases the CHD risk in a Han Chinese population, providing new insights into CHD aetiology.
