Gene Variants Implicated in Bicuspid Aortic Valve Development

Results presented in a recently published paper identified genetic variants associated with the formation of bicuspid aortic valve (BAV), a common congenital heart defect.

Individuals with BAV have aortic valves with only two leaflets, rather than three, limiting the valve’s function. The condition is associated with various complications, including a narrowed valve (aortic stenosis), a leaky valve (aortic insufficiency or regurgitation), infection of the valve, or aortic aneurysm. The genetic basis for BAV is only poorly understood.


Investigators at the University of Michigan (Ann Arbor, USA) performed a genome-wide association scan of 466 BAV cases and 4,660 age, sex, and ethnicity-matched controls with replication in up to 1,326 cases and 8,103 controls.

The investigators reported in the May 25, 2017, online edition of the journal Nature Communications that they identified association with a noncoding variant 151 kilobases from the gene encoding the cardiac-specific transcription factor, GATA4. GATA4 is a critical transcription factor for proper mammalian cardiac development and essential for survival of the embryo.

To further examine the link between BAV and GATA4, the investigators used CRISPR/Cas9 gene editing to abolish GATA4 activity in stem cells that were derived from mature leukocytes taken from normal subjects.

CRISPRs (clustered regularly interspaced short palindromic repeats) are segments of prokaryotic DNA containing short repetitions of base sequences. Each repetition is followed by short segments of "spacer DNA" from previous exposures to a bacterial virus or plasmid. CRISPRs are found in approximately 40% of sequenced bacteria genomes and 90% of sequenced archaea. CRISPRs are often associated with cas genes that code for proteins related to CRISPRs. Since 2013, the CRISPR/Cas system has been used in research for gene editing (adding, disrupting, or changing the sequence of specific genes) and gene regulation. By delivering the Cas9 enzyme and appropriate guide RNAs (sgRNAs) into a cell, the organism's genome can be cut at any desired location.

The investigators reported that disruption of GATA4 by CRISPR/Cas9 significantly impaired the transition of stem cells from endothelial cells into mesenchymal cells, a critical step in heart valve development.

“One of the regions we identify actually changes the protein coded by the gene, and the other likely changes expression levels of GATA4 during valve formation,” said senior author Dr. Cristen Willer, professor of internal medicine, human genetics, and computational medicine and bioinformatics at the University of Michigan. “Because most genetic variants associated with human disease are in the 99% of the genome that does not code for proteins, this finding gives us a great head start toward understanding the mechanism of how a genetic change outside the protein-coding part of the genome can lead to disease.”

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