Role of the ADCY9 gene in cardiac abnormalities of the Rubinstein-Taybi syndrome

Abstract

Background: Rubinstein-Taybi syndrome (RTS) is a rare, congenital, plurimalformative, and neurodevelopmental disorder. Previous studies have reported that large deletions contribute to more severe RTS phenotypes than those caused by CREBBP point mutations, suggesting a concurrent pathogenetic role of flanking genes, typical of contiguous gene syndromes, but the detailed genetics are unclear. Results: This study presented a rare case of Rubinstein-Taybi (RT) syndrome with serious cardiac abnormalities. Based on the clinical and genetic analysis of the patient, the ADCY9 gene deletion was highlighted as a plausible explanation of cardiac abnormalities. In adcy9 morphant zebrafish, cardiac malformation was observed. Immunofluorescence study disclosed increased macrophage migration and cardiac apoptosis. RNA sequencing in zebrafish model highlighted the changes of a number of genes, including increased expression of the mmp9 gene which encodes a matrix metalloproteinase with the main function to degrade and remodel extracellular matrix. Conclusions: In this study, we identified a plausible new candidate gene ADCY9 of CHD through the clinical and genetic analysis of a rare case of Rubinstein-Taybi (RT) syndrome with serious cardiac abnormalities. By functional study of zebrafish, we demonstrated that deletion of adcy9 is the causation for the cardiac abnormalities. Cardiac apoptosis and increased expression of the MMP9 gene are involved in the pathogenesis.

ADCY9 functions as a novel cancer suppressor gene in lung adenocarcinoma

“…Downregulation of ADCY9 is related to positive effects on atherosclerosis and cardiovascular endothelial function and a gain in adipose tissue volume in the absence of CETP ( 18 , 41 ). Apart from cardiovascular disease, the ADCY9 gene is linked to Rubinstein-Taybi syndrome, a rare congenital, plural formative, and neurodevelopmental disorder ( 42 ). Previous research into ADCY9 also validated that its expression level is associated with poor prognosis in colorectal cancer, hepatocellular carcinoma, and glioma occurrence ( 43 - 45 ).…”

Novel and Annotated Long Noncoding RNAs Associated with Ischemia in the Human Heart

“…Several of the protein-coding genes in Module 1 have already been demonstrated to be associated with cardiac energy metabolism and apoptosis such as 2-oxoglutarate dehydrogenase (OGDH), a potent source of reactive oxygen species (ROS) in cardiac mitochondria [ 17 ]. Additionally, in the same module, we identified Mitofusin-2 (MFN2), involved in mitochondrial integrity and protecting cardiomyocytes during ischemia-reperfusion injury [ 18 ] and Adenylate Cyclase 9 (ADCY9), involved in cardiac apoptosis [ 19 ].…”