Abstract
Background: Cardiac development is a dynamic process both temporally and spatially. These complex processes are often disturbed and lead to congenital cardiac anomalies that affect approximately 1% of live births. Disease-causing variants in several genetic loci lead to cardiac anomalies, with variants in transcription factor NKX2-5 gene being one of the largest variants known. Gestational hypoxia, such as seen in high-altitude pregnancy, has been known to affect cardiac development, yet the incidence and underlying mechanisms are largely unknown.Methods and Results: Normal wild-type female mice mated with heterozygous Nkx2-5 mutant males were housed under moderate hypoxia (14% O2) or normoxia (20.9% O2) conditions from 10.5 days of gestation. Wild-type mice exposed to hypoxia demonstrate excessive trabeculation, ventricular septal defects, irregular morphology of interventricular septum as well as atrial septal abnormalities, which overlap with those seen in heterozygous Nkx2-5 mutant mice. Genome-wide transcriptome done by RNA-seq of a 2-day hypoxic exposure on wild-type embryos revealed abnormal transcriptomes, in which approximately 60% share those from Nkx2-5 mutants without hypoxia. Gestational hypoxia reduced the expression of Nkx2-5 proteins in more than one-half along with a reduction in phosphorylation, suggesting that abnormal Nkx2-5 function is a common mechanism shared between genetic and gestational hypoxia-induced cardiac anomalies, at least at a specific developing stage.Conclusion: The results of our study provide insights into a common molecular mechanism underlying non-genetic and genetic cardiac anomalies.
Highlights
Congenital cardiac anomalies are the most prevalent birth defects, affecting approximately 1% of live births [1,2,3]
Familial congenital cardiac malformations due to a heterozygous NKX2-5 diseasecausing variant are one of the largest sets of genetic mutations related to cardiac malformations (OMIM, NCBI), and currently nearly 40 heterozygous variants have been reported in humans [5,6,7]
We examined gestational hypoxia-induced murine cardiac anomalies using a physiological level of hypoxia of 14% oxygen concentration, and found an interaction between non-genetic and genetic cardiac anomalies induced by the abnormal function of Nkx2-5
Summary
Congenital cardiac anomalies are the most prevalent birth defects, affecting approximately 1% of live births [1,2,3]. But a varied range of severity of cardiac anomalies was demonstrated in Nkx mutant mice that have a single point mutation identified in human patients, and have a nearly identical genetic background by backcrossing [8]. These results suggest that non-genetic factors, influence cardiac malformations. Disease-causing variants in several genetic loci lead to cardiac anomalies, with variants in transcription factor NKX2-5 gene being one of the largest variants known Gestational hypoxia, such as seen in high-altitude pregnancy, has been known to affect cardiac development, yet the incidence and underlying mechanisms are largely unknown
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