Nav: Home

One gene mutation, two diseases, many insights into human heart function

December 15, 2016

Scientists at the Gladstone Institutes linked a single gene mutation to two types of heart disease: one causes a hole in the heart of infants, and the other causes heart failure. Using cells donated by a family with the mutation, the researchers gained insight into congenital heart disease, human heart development, and healthy heart function.

"Studying what goes wrong in disease can provide us with important insights into basic biology and how it's supposed to go right," said Deepak Srivastava, MD, director of the Gladstone Institute of Cardiovascular Disease and senior author on the new study. "The lessons we learned about cardiac gene networks from this family and their mutation will inform the development of treatments not only for their form of heart disease, but for many others."

A Family Affair: Gene Mutations and Congenital Heart Disease

Congenital heart disease afflicts almost one percent of all newborn babies. In a particularly common type, a hole forms in the wall (called the septum) between two chambers of the heart. One cause of these septal defects is a mutation in the GATA4 gene, which is essential for normal heart development and healthy heart function. The GATA4 gene encodes a "master regulator" protein of the same name that activates or silences other genes involved in heart development.

The current study, published in the journal Cell, involved a family of patients who suffer from congenital heart disease and carry a mutation in GATA4. The family first approached Srivastava in 2003 after half of the babies in the family were born with a septal defect. Using gene sequencing, the researchers learned that every member of the family with congenital heart disease had the same mutation in GATA4--a change in a single letter in the gene.

Seven years later, several of the family members, now adolescents, developed a separate disease of the heart muscle that caused it to pump abnormally. The scientists concluded that the same GATA4 mutation was to blame for the heart muscle dysfunction, but they did not know why.

GATA4 Cause and Effect

To answer this question, the Srivastava team took skin cells from the family and reprogrammed them using stem cell technology into beating heart cells. This technique enabled the scientists to study heart cells with an identical genetic make-up as the patients to determine how the GATA4 mutation was causing the two forms of disease.

The scientists noticed several abnormalities in the heart cells created from the patients: the cells beat weaker than normal, and numerous genes in the cells were abnormally activated or silenced. For example, genes involved in heart formation were not properly turned on, including genes that control septum formation. In contrast, genes involved in the development of other organs were turned on when they should have been off.

"By studying the patients' heart cells in a dish, we were able to figure out why their hearts were not pumping properly," explained Srivastava. "Investigating their genetic mutation revealed a whole network of genes that went awry, first causing septal defects and then the heart muscle dysfunction."

The researchers discovered that the GATA4 mutation prevented another master regulator protein, TBX5, from being recruited to genes needed for heart development and muscle contraction. GATA4 and TBX5 work together to activate genes responsible for heart formation and function, and silence genes involved in other organs. However, if one protein is mutated, then the other does not work well. Because of the single mutation in GATA4, virtually the entire network of genes regulated by GATA4 and TBX5 were disrupted, resulting in disease. Interestingly, human mutations in TBX5 also result in holes in the heart.

"It was surprising how widespread the effect was. We changed one letter in one gene, and the entire cardiac development process was upended," said first author Yen-Sin Ang, PhD, a research scientist at Gladstone. "This work reveals how a single mutation in a key cardiac gene can lead to at least two forms of disease."

Deep Probe Opens Door to Treatment

It is difficult to target master regulator proteins, such as GATA4, with drugs because their influence is so widespread. However, the researchers did find a potential therapeutic target downstream of GATA4 that might be used to treat heart disease.

Using computational modeling to extend their research in the cells, the scientists identified a hub of genes controlled by GATA4 that is important for heart function. They think this gene hub could be targeted with drugs to correct some of the damage caused by GATA4 mutations. Notably, a drug that affects this pathway already exists, and the researchers are pursuing it as a potential treatment for heart disease.

"It's amazing that by studying genes in a two-dimensional cluster of heart cells, we were able to discover insights into a disease that affects a complicated three-dimensional organ," said Ang. "We think this conceptual framework could be used to study other diseases caused by mutations in proteins that serve as master regulators of whole gene networks."
Other Gladstone researchers on the study include Renee Rivas, Janell Rivera, Nicole Stone, Karishma Pratt, Tamer Mohamed, Ji-Dong Fu, Ian Spencer, Molong Li, and Ethan Radzinsky. Rohith Srivas, Michael Snyder, Alexandre Ribeiro and Beth Pruitt from Stanford University, and scientists from the University of California, San Francisco, and Cornell University also contributed to the research.

Gladstone Institutes

Related Heart Disease Articles:

Arsenic in drinking water may change heart structure raising risk of heart disease
Drinking water that is contaminated with arsenic may lead to thickening of the heart's main pumping chamber in young adults, according to a new study by researchers at Columbia University Mailman School of Public Health.
New health calculator can help predict heart disease risk, estimate heart age
A new online health calculator can help people determine their risk of heart disease, as well as their heart age, accounting for sociodemographic factors such as ethnicity, sense of belonging and education, as well as health status and lifestyle behaviors.
Wide variation in rate of death between VA hospitals for patients with heart disease, heart failure
Death rates for veterans with ischemic heart disease and chronic heart failure varied widely across the Veterans Affairs (VA) health care system from 2010 to 2014, which could suggest differences in the quality of cardiovascular health care provided by VA medical centers.
Heart failure: The Alzheimer's disease of the heart?
Similar to how protein clumps build up in the brain in people with some neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, protein clumps appear to accumulate in the diseased hearts of mice and people with heart failure, according to a team led by Johns Hopkins University researchers.
Women once considered low risk for heart disease show evidence of previous heart attack scars
Women who complain about chest pain often are reassured by their doctors that there is no reason to worry because their angiograms show that the women don't have blockages in the major heart arteries, a primary cause of heart attacks in men.
Where you live could determine risk of heart attack, stroke or dying of heart disease
People living in parts of Ontario with better access to preventive health care had lower rates of cardiac events compared to residents of regions with less access, found a new study published in CMAJ (Canadian Medical Association Journal).
Older adults with heart disease can become more independent and heart healthy with physical activity
Improving physical function among older adults with heart disease helps heart health and even the oldest have a better quality of life and greater independence.
Dietary factors associated with substantial proportion of deaths from heart disease, stroke, and disease
Nearly half of all deaths due to heart disease, stroke, and type 2 diabetes in the US in 2012 were associated with suboptimal consumption of certain dietary factors, according to a study appearing in the March 7 issue of JAMA.
Certain heart fat associated with higher risk of heart disease in postmenopausal women
For the first time, researchers have pinpointed a type of heart fat, linked it to a risk factor for heart disease and shown that menopausal status and estrogen levels are critical modifying factors of its associated risk in women.
Maternal chronic disease linked to higher rates of congenital heart disease in babies
Pregnant women with congenital heart defects or type 2 diabetes have a higher risk of giving birth to babies with severe congenital heart disease and should be monitored closely in the prenatal period, according to a study published in CMAJ.
More Heart Disease News and Heart Disease Current Events

Top Science Podcasts

We have hand picked the top science podcasts of 2019.
Now Playing: TED Radio Hour

Why do we revere risk-takers, even when their actions terrify us? Why are some better at taking risks than others? This hour, TED speakers explore the alluring, dangerous, and calculated sides of risk. Guests include professional rock climber Alex Honnold, economist Mariana Mazzucato, psychology researcher Kashfia Rahman, structural engineer and bridge designer Ian Firth, and risk intelligence expert Dylan Evans.
Now Playing: Science for the People

#540 Specialize? Or Generalize?
Ever been called a "jack of all trades, master of none"? The world loves to elevate specialists, people who drill deep into a single topic. Those people are great. But there's a place for generalists too, argues David Epstein. Jacks of all trades are often more successful than specialists. And he's got science to back it up. We talk with Epstein about his latest book, "Range: Why Generalists Triumph in a Specialized World".
Now Playing: Radiolab

Dolly Parton's America: Neon Moss
Today on Radiolab, we're bringing you the fourth episode of Jad's special series, Dolly Parton's America. In this episode, Jad goes back up the mountain to visit Dolly's actual Tennessee mountain home, where she tells stories about her first trips out of the holler. Back on the mountaintop, standing under the rain by the Little Pigeon River, the trip triggers memories of Jad's first visit to his father's childhood home, and opens the gateway to dizzying stories of music and migration. Support Radiolab today at