HAND1 loss-of-function mutation contributes to congenital double outlet right ventricle

Abstract

Congenital heart defects (CHDs), a wide variety of developmental abnormalities in the structures of the heart and the great thoracic blood vessels, are the most common form of birth defect in humans worldwide. CHDs are accountable for substantial morbidity and are still the leading cause of birth defect‑related deaths. Recent studies have demonstrated the pivotal roles of genetic defects in the pathogenesis of CHDs, and a great number of genetic mutations have been associated with CHDs. Nevertheless, CHDs are a genetically heterogeneous disorder and the genetic basis underlying CHDs in an overwhelming majority of cases remains unclear. In the present study, the coding exons and flanking introns of the heart and neural crest derivatives expressed transcript 1 (HAND1) gene, which encodes a basic helix‑loop‑helix transcription factor crucial for cardiovascular development, were sequenced in 158 unrelated patients with CHDs, and a de novo heterozygous mutation, p.K132X, was identified in a patient with double outlet right ventricle (DORV), as well as ventricular septal defect. The nonsense mutation, which was predicted to produce a truncated HAND1 protein lacking 84 carboxyl‑terminal amino acids, was absent in 600 control chromosomes. Functional analyses revealed that the HAND1 K132X mutant had no transcriptional activity. Furthermore, the mutation disrupted the synergistic activation between HAND1 and GATA binding protein 4 (GATA4), another cardiac core transcription factor causally linked to CHDs. To the best of our knowledge, this is the first report on the association of HAND1 loss‑of‑function mutation with an enhanced susceptibility to DORV in humans. These findings expand the phenotypic spectrum linked to HAND1 mutations, suggesting potential implications for the development of novelo prophylactic and therapeutic strategies for DORV.

Prenatal delta-9-tetrahydrocannabinol exposure is associated with changes in rhesus macaque DNA methylation enriched for autism genes

“…Loss of this gene in mice is associated with increased anxiety-related behavior in certain tasks such as spending 50% less time in the open arms of the elevated plus maze [ 60 ]. In the right ventricle of the heart, we identified FDR significant hypomethylation of one CpG upstream of the heart and neural crest derivatives expressed 1 ( HAND1 ) gene, which is essential to the formation of the right ventricle [ 61 ]. Additionally in the right ventricle, we observed hypermethylation of one CpG annotated to the neutral sphingomyelinase activation associated factor gene ( NSMAF) , which may play a role in activation of neutral sphingomyelinase in response to cardiac ischemia or reperfusion injury [ 62 ].…”

Identification of Target Genes in Hypertension and Left Ventricular Remodeling

“…HAND1 plays important roles in both cardiac morphogenesis and trophoblast-giant cells differentiation. [ 34 ] It may also affect septal defects in the human heart, thereby playing wider roles in human congenital heart diseases. [ 35 ] CREB, significantly increased in LVH, [ 36 ] not only contributing to the primary modulating factors of the endoplasmic reticulum stress regulating, but also stimulating transcription upon binding to the DNA cAMP response element.…”

Congenital heart diseases: genetics, non-inherited risk factors, and signaling pathways

“…Mutations in other several genes have been reported to be associated with congenital heart diseases. These genes include the following: ankyrin repeat domain 1 (ANKRD1) associated with septal defects, NR2F2 gene associated with double outlet ventricle, HAND2 gene associated with familial ventral septal defect, pulmonary stenosis, double outlet right ventricle, tetralogy of Fallot, and CASZ1 gene associated with the ventral septal defects [112][113][114][115][116].…”