MESP1 lossoffunction mutation contributes to double outlet right ventricle.
Mol Med Rep
; 16(3): 2747-2754, 2017 Sep.
Article
em En
| MEDLINE
| ID: mdl-28677747
ABSTRACT
Congenital heart disease (CHD) is the most common form of birth defect in humans, and remains a leading noninfectious 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 helixloophelix 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, ethnicallymatched healthy individuals, who were used as controls, were genotyped for MESP1. The functional characteristics of the MESP1 mutation were determined using a dualluciferase 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 wildtype counterpart. The present study firstly provided experimental evidence supporting the concept that a MESP1 lossoffunction 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Dupla Via de Saída do Ventrículo Direito
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Mutação de Sentido Incorreto
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Fatores de Transcrição Hélice-Alça-Hélice Básicos
Tipo de estudo:
Prognostic_studies
Limite:
Adolescent
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Adult
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Animals
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Child
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Child, preschool
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Female
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Humans
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Infant
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Male
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Newborn
Idioma:
En
Revista:
Mol Med Rep
Ano de publicação:
2017
Tipo de documento:
Article