Risk factors for congenital heart defects may lie both inside and outside the heart

September 8, 2016
Optical projection tomography of an E10.5 Nipbl+/- mouse embryo shows, on the left, a three-dimensional reconstruction of the embryo with heart highlighted in red; on the right is an optical section through the heart showing an abnormally small right ventricle. Credit: Benedikt Hallgrimsson/University of Calgary

Congenital heart defects (CHDs) are a leading cause of birth defect-related deaths. Understanding how genetic alterations cause such defects is complicated by the fact that many of the critical genes are unknown, and those that are known often contribute only small increases in CHD risk.

In new research publishing Sept. 8 in the Open Access journal PLOS Biology, University of California, Irvine biologists Anne Calof and Arthur Lander and colleagues report that the role of genes in CHD is more complex than previously realized and that overall risk is determined by a combination of gene effects both inside and outside of the heart itself.

Normal heart formation depends on interactions of multiple types of cells that collaborate in precise times and places throughout development to build the heart's intricate structures. To figure out how these interactions can go awry, the Calof-Lander team studied atrial septal defects (ASDs, a common type of heart defect) in a mouse model of the developmental disorder Cornelia de Lange Syndrome (CdLS).

Most cases of Cornelia de Lange Syndrome are caused by mutations that inactivate a single copy of Nipbl, a gene that directs the expression of many hundreds of other genes in tissues throughout the body. Just as people with Cornelia de Lange Syndrome have a high incidence of heart defects, 30 percent of mice that harbor similar Nipbl mutations exhibit atrial septal defects.

Employing genetically modified mouse models, the researchers used a novel technology to selectively introduce or remove Nipbl mutations in different tissues during embryonic development. Unexpectedly, they found that no Nipbl deficiency in any single tissue—including the tissue that forms the heart itself—could singlehandedly account for the development of atrial septal defects. Rather, the development of heart defects was determined by interactions between heart-forming tissues and the rest of the body. In fact, Nipbl deficiency in some tissues even seemed to protect against the development of atrial septal defects, in certain situations.

In a Primer article that accompanies this research, Bruce Gelb, MD, from the Icahn School of Medicine at Mount Sinai, explains why these were "mind-bending results" and writes that "this work provides novel insights into incomplete penetrance and oligogenic effects underlying CHD." He adds that the novel observations "add further complexity to the way in which we need to think about CHD pathogenesis".

"Our results lead us to hypothesize that heart defects such as ASDs occur when the heart does not grow quickly enough to meet the demands of the developing body - in other words, that heart size and body size must be coordinated for the heart to develop without defects," said Calof, professor of anatomy & neurobiology and developmental & cell biology at UCI. "To our knowledge, this is the first genetic demonstration that major risk factors for are likely to lie outside of the heart itself."

"When a single gene change causes a birth defect, we often assume that it's because one thing goes wrong in one cell type. The big difference in our studies may have to do with the fact that Nipbl controls a large number of other genes," said Lander, the Donald Bren Professor of Developmental & Cell Biology and director of UCI's Center for Complex Biological Systems. "Given that most human CHDs are now thought to be caused by gene variants acting in combination, what we learned from Nipbl-deficient mice may actually be more typical of the way most CHDs arise."

Explore further: Zebrafish study sheds new light on human heart defects

More information: PLOS Biology, dx.doi.org/10.1371/journal.pbio.2000197

Related Stories

Zebrafish study sheds new light on human heart defects

October 16, 2015
University of Otago researchers working with zebrafish have published a study providing new insights into the causes of the congenital heart defects associated with a rare developmental disorder.

Folic acid fortified food linked to decline in congenital heart defects

August 29, 2016
Food fortified with folic acid, a B vitamin required in human diets for numerous biological functions, was associated with reduced rates of congenital heart defects, according to new research in the American Heart Association's ...

New mouse model helps explain gene discovery in congenital heart disease

June 26, 2012
Scientists now have clues to how a gene mutation discovered in families affected with congenital heart disease leads to underdevelopment of the walls that separate the heart into four chambers. A Nationwide Children's Hospital ...

Adults born with heart disease have increased risk of developing type 2 diabetes

July 19, 2016
Children born with heart disease have an increased risk of developing type 2 diabetes after age 30, according to a new study.

New rare congenital heart disease disorders found in children

August 1, 2016
In one of the largest international genetic studies of congenital heart disease (CHD), researchers have discovered gene mutations linked to three new rare congenital heart disorders. Published in Nature Genetics today, the ...

World first discovery gets to the heart of birth defects

July 20, 2016
For the first time, scientists believe they've discovered a cause of multiple types of birth defects triggered by environmental stresses.

Recommended for you

Could aggressive blood pressure treatments lead to kidney damage?

July 18, 2017
Aggressive combination treatments for high blood pressure that are intended to protect the kidneys may actually be damaging the organs, new research from the University of Virginia School of Medicine suggests.

Quantifying effectiveness of treatment for irregular heartbeat

July 17, 2017
In a small proof-of-concept study, researchers at Johns Hopkins report a complex mathematical method to measure electrical communications within the heart can successfully predict the effectiveness of catheter ablation, the ...

Concerns over side effects of statins stopping stroke survivors taking medication

July 17, 2017
Negative media coverage of the side effects associated with taking statins, and patients' own experiences of taking the drugs, are among the reasons cited by stroke survivors and their carers for stopping taking potentially ...

Study discovers anticoagulant drugs are being prescribed against safety advice

July 17, 2017
A study by researchers at the University of Birmingham has shown that GPs are prescribing anticoagulants to patients with an irregular heartbeat against official safety advice.

Protein may protect against heart attack

July 14, 2017
DDK3 could be used as a new therapy to stop the build-up of fatty material inside the arteries

Heart study finds faulty link between biomarkers and clinical outcomes

July 14, 2017
Surrogate endpoints (biomarkers), which are routinely used in clinical research to test new drugs, should not be trusted as the ultimate measure to approve new health interventions in cardiovascular medicine, according to ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.