MESP1 loss‑of‑function mutation contributes to double outlet right ventricle

Congenital heart disease (CHD) is the most common form of birth defect in humans, and remains a leading non‑infectious cause of infant mortality worldwide. An increasing number of studies have demonstrated that genetic defects serve a pivotal role in the pathogenesis of CHD, and mutations in >60 genes have been causally associated with CHD. CHD is a heterogeneous disease and the genetic basis of CHD in the majority of patients remains poorly understood. In the present study, the coding exons and flanking introns of the mesoderm posterior 1 (MESP1) gene, which encodes a basic helix‑loop‑helix transcription factor required for normal cardiovascular development, were sequenced in 178 unrelated patients with CHD. The available relatives of the index patient carrying an identified mutation and 200 unrelated, ethnically‑matched healthy individuals, who were used as controls, were genotyped for MESP1. The functional characteristics of the MESP1 mutation were determined using a dual‑luciferase reporter assay system. As a result, a novel de novo heterozygous MESP1 mutation, p.Q118X, was identified in an index patient with double outlet right ventricle (DORV) and a ventricular septal defect. The nonsense mutation was absent in the 400 reference chromosomes and the altered amino acid was completely conserved evolutionarily across species. Functional assays indicated that the mutant MESP1 protein had no transcriptional activity when compared with its wild‑type counterpart. The present study firstly provided experimental evidence supporting the concept that a MESP1 loss‑of‑function mutation may contribute to the development of DORV in humans, which presents a significant insight into the molecular pathogenesis of CHD. The results highlight the potential implications for the genetic counseling and personalized treatment of patients with CHD.