PUBLICATION
Identification of KIAA0196 as a novel susceptibility gene for myofibril structural disorganization in cardiac development
- Authors
- Bu, H., Yang, Y., Wu, Q., Tan, Z., Gong, X., Hu, S., Zhao, T.
- ID
- ZDB-PUB-200518-12
- Date
- 2020
- Source
- International Journal of Cardiology 314: 81-88 (Journal)
- Registered Authors
- Keywords
- Cardiac development, Cardiac function, KIAA0196, Mouse, Myofibrils structure, Zebrafish
- MeSH Terms
-
- Animals
- Heart
- Mice
- Myofibrils*
- Sarcomeres
- Zebrafish*/genetics
- Zebrafish Proteins
- PubMed
- 32417190 Full text @ Int. J. Cardiol.
Citation
Bu, H., Yang, Y., Wu, Q., Tan, Z., Gong, X., Hu, S., Zhao, T. (2020) Identification of KIAA0196 as a novel susceptibility gene for myofibril structural disorganization in cardiac development. International Journal of Cardiology. 314:81-88.
Abstract
Background Congenital heart disease is one of the most common cardiac malformation-related diseases worldwide. Some causative genes have been identified but can explain only a small proportion of all cases; therefore, the discovery of novel susceptibility genes and/or modifier genes for abnormal cardiac development remains a major challenge.
Methods We used a single nucleotide polymorphism (SNP) array, and next-generation sequencing (NGS) was conducted to screen and quickly identify candidate genes. KIAA0196 knockout zebrafish and mice were generated by CRISPR/Cas9 to detect whether or how KIAA0196 deficiency would influence cardiac development.
Results Homozygous, but not heterozygous, zebrafish and mice showed early embryonic lethality. At the embryonic stage, microscopic examination and dissection revealed pericardial edema and ventricle enlargement in homozygous zebrafish and obviously delayed cardiac development in heterozygous mice, while echocardiography and tissue staining showed that significantly decreased cardiac function, ventricle enlargement, myofibril loss, and significantly reduced trabecular muscle density were observed in adult heterozygous zebrafish and mice. Most importantly, immunostaining and electron microscopy showed that there was a significant increase in sarcomere structural disorganization and myofibril structural integrity loss in KIAA0196 mutants. Furthermore, substantial downregulation in other sarcomeric genes and proteins was detected and verified in a mouse model via transcriptome and proteomics analyses; these changes especially affected the myosin heavy or light chain (MYH or MYL) family genes.
Conclusion We identified KIAA0196 for the first time as a susceptibility gene for abnormal cardiac development. KIAA0196 deficiency may cause abnormal heart development by influencing the structural integrity of myofibrils.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping