Medical Professional Publications

Study Finds loss of NOTCH1 Gene Appears to Cause Ascending Aortic Aneurysm

(From the December 2017 issue of Research Now)

Understanding the gene’s role may enable physicians to predict children at risk and develop therapies, researchers say

Mutations in the NOTCH1 gene may contribute to the development of ascending aortic aneurysm (AscAA), which when it ruptures carries a high risk of death, a study led by Nationwide Children’s Hospital researchers shows.

Using a mouse model, the researchers deleted half of the NOTCH1 gene from second heart field cells, which are progenitor cells that contribute to the aortic wall. They found ascending aortic dilation increased and in some cases resulted in aortic rupture.

The study is the first, researchers believe, to show a specific role for NOTCH1 in second heart field cells in the development of AscAA.

The team expects the findings, reported in JCI Insight, to be a step toward identifying therapeutic targets to correct or control the condition.  NOTCH1 plays an essential role in the Notch signaling pathway that regulates interactions between adjacent cells and the development of many cell types.

“If we understand the genetics of aortic aneurysms, we hope that 5 to 10 years down the road we can predict who is at risk,” said Vidu Garg, MD, director of the Center for Cardiovascular Research in The Research Institute at Nationwide Children’s.

In earlier work, Dr. Garg discovered NOTCH1 mutations among two families with bicuspid aortic valve disease. Several of family members also had aortic aneurysms, which made Dr. Garg’s team suspect a common link – a gene that is important for both diseases.

Other studies, including work from Dr. Garg’s lab, had already demonstrated the role for NOTCH1 in the development of bicuspid aortic valve, and Dr. Garg’s team thought the protein-producing gene was a possible culprit for AscAA.

In this new study using a Marfan syndrome mouse which is used to model AscAA, the researchers, led by Sara Koenig, BA a graduate student in Dr. Garg’s lab, discovered that deleting half of the NOTCH1 gene, called a heterozygous deletion, resulted in more severe aortic root dilation in the setting of a normal three leaflet aortic valve.

Heterozygous deletion in mature smooth muscle, endothelial and cardiac neural crest cells had found no effect on the AscAA in the Marfan syndrome mouse model, but heterozygous deletion in second heart field cells exacerbated the AscAA phenotype. The researchers think that the lack of NOTCH1 likely alters the formation of the aortic root, leaving it susceptible to dilation and rupture. 

The team is now investigating specifically what the loss of NOTCH1 does and how it directly changes regulation of aortic wall development using a new mouse model of Notch1 heterozygous deletion, which is also described in this publication.

In addition, the study suggests that individuals with NOTCH1 mutations may have a high risk for AscAA and may be candidates for earlier surgical intervention.

Because the heart develops during the first trimester, a genetic solution is unlikely, Dr. Garg says. “But, if we understand how the disease occurs, we may be able to develop pharmacologic therapies to do what a healthy NOTCH1 does.”

Citation: Koenig SN, LaHaye S, Feller JD, Rowland P, Hor KN, Trask AJ, Janssen PM, Radtke F, Lilly B, Garg V. Notch1 haploinsufficiency causes ascending aortic aneurysms in mice. JCI Insight. 2017 Nov 2;2(21). pii: 91353. doi: 10.1172/JCI Insight.91353. [Epub ahead of print]

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