Characterization of Transcriptional Repressor Gene MSX1 Variations for Possible Associations with Congenital Heart Diseases.

Fei-Feng Li,Qing-Liang Shao,Jing Zhou,Xue-Qi Li,Xia Li,Xi-Dong Zhu,Ying Han,Shu-Lin Liu,Shuai Shi,Austin John Cooney

doi:10.1371/journal.pone.0142666

Abstract

BackgroundThe human heart consists of several cell types with distinct lineage origins. Interactions between these cardiac progenitors are very important for heart formation. The muscle segment homeobox gene family plays a key role in the cell morphogenesis and growth, controlled cellular proliferation, differentiation, and apoptosis, but the relationships between the genetic abnormalities and CHD phenotypes still remain largely unknown. The aim of this work was to evaluate variations in MSX1 and MSX2 for their possible associations with CHD.MethodsWe sequenced the MSX1 and MSX2 genes for 300 Chinese Han CHD patients and 400 normal controls and identified the variations. The statistical analyses were conducted using Chi-Square Tests as implemented in SPSS (version 19.0). The Hardy-Weinberg equilibrium test of the population was carried out using the online software OEGE.ResultsSix variations rs4647952, rs2048152, rs4242182, rs61739543, rs111542301 and rs3087539 were identified in the MSX2 gene, but the genetic heterozygosity of those SNPs was very low. In contrast, the genetic heterozygosity of two variations rs3821949 near the 5’UTR and rs12532 within 3’UTR of the MSX1 gene was considerably high. Statistical analyses showed that rs3821949 and rs12532 were associated with the risk of CHD (specifically VSD).ConclusionsThe SNPs rs3821949 and rs12532 in the MSX1 gene were associated with CHD in Chinese Han populations.

Highlights

Congenital heart diseases (CHD) are a group of complex congenital anatomic malformations worldwide with high morbidity and mortality
Statistical analyses showed that rs3821949 and rs12532 were associated with the risk of CHD ( ventricular septal defects (VSD))
The single nucleotide polymorphisms (SNPs) rs3821949 and rs12532 in the Muscle segment homeobox 1 (MSX1) gene were associated with CHD in Chinese Han populations

Summary

Introduction

Congenital heart diseases (CHD) are a group of complex congenital anatomic malformations worldwide with high morbidity and mortality. The Nodal/TGF-βsignaling pathway has a key role in early stages of human embryonic stem (HES) cell differentiation, directing the cells to develop into different embryonic lineages. SMAD3, an intracellular regulating factor in the Nodal/TGF-β signaling pathway to modulate the transcription of many genes [15, 16], together with LEFTY plays central roles in the signaling pathway [15, 17]. As the process of HES cell differentiation during embryonic development is very important for the heart development, it may be involved in the pathogenesis of CHDs. The human heart consists of several cell types with distinct lineage origins. The muscle segment homeobox gene family plays a key role in the cell morphogenesis and growth, controlled cellular proliferation, differentiation, and apoptosis, but the relationships between the genetic abnormalities and CHD phenotypes still remain largely unknown. The aim of this work was to evaluate variations in MSX1 and MSX2 for their possible associations with CHD

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