PUBLICATION

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

Authors
Wu, Y., Xia, Y., Li, P., Qu, H.Q., Liu, Y., Yang, Y., Lin, J., Zheng, M., Tian, L., Wu, Z., Huang, S., Qin, X., Zhou, X., Chen, S., Liu, Y., Wang, Y., Li, X., Zeng, H., Hakonarson, H., Zhuang, J.
ID
ZDB-PUB-200424-1
Date
2020
Source
Orphanet journal of rare diseases   15: 101 (Journal)
Registered Authors
Keywords
ADCY9, Congenital heart defects, MMP9, Rubinstein-Taybi syndrome
MeSH Terms
  • Animals
  • CREB-Binding Protein/genetics
  • Gene Deletion
  • Humans
  • Phenotype
  • Rubinstein-Taybi Syndrome*/genetics
  • Zebrafish/genetics
PubMed
32321550 Full text @ Orphanet J Rare Dis
Abstract
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.
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.
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping