- Scientists from
Gladstone Institute of Cardiology have identified a single mutation in GATA4 gene that is found to
lead to two different heart diseases.
- A hole in the septum
of the heart is found in newborns and in adolescents, there is heart muscle
- Study provides key insight into developmental
stages of the heart as well as mediators of heart function
A rare gene mutation has
now been found to be associated with two heart conditions, one in which there
is a hole in the heart and another one that causes heart disease. The study was
conducted on cells that were donated by a family with this congenital
The single gene mutation
that leads to heart complications allowed the scientists to gain key insights
into human heart development and function. The lead author of the study, Dr.
Deepak Srivastava who is the Director of Gladstone Institute of Cardiology said
that the information gathered from the donor cells provided information about
the congenital disorder suffered by the family as well as information on other
‘Identifying GATA4 gene targets will aid in treatment of Congenital Heart Diseases.’
and a hole in the heart
A mutation in the GATA4
(GATA Binding Protein 4) gene results in a hole
in the septum of the heart that separates the two chambers. This gene affects
the production of the protein called GATA4, which is considered a master
regulator as this protein silences or activates other genes that are involved
in the development of the heart.
A congenital heart defect
a condition that exists from birth. They are the leading cause of
non-infectious mortality among newborns with a prevalence of 4 to 8 per 1000
live births. A serious defect among newborns may be identified by the following
- A bluish tint called cyanosis in
the fingernails, lips and the skin
- Poor blood
Many congenital heart
defects do not require interventions till the child is older; however, certain
congenital heart defects require immediate support. Though there is a large
prevalence of congenital heart defects, the exact etiology of the condition is
not yet well understood.
Dr. Srivastava first met
the family in 2003, when they approached him with septal defects in nearly half
of the babies born in their family. This lead the doctor to initiate gene
sequencing practices that were used to identify the mutations that lead to this
congenital disorder. In all the family members with this disorder, it was found
that there was a single gene mutation in GATA4.
When these babies grew
into adolescence, they developed weakening of the heart muscles of unknown
origin. The researchers then hypothesized that the same gene mutation that
caused a hole in the septum of the heart of babies, resulted in heart muscle
weakening as they grew older.
Gene Mutation in Action
The scientists used stem
cell technology to reprogram the cells and convert them into beating heart
cells. This led to the development of heart cells with the genetic mutation
that was identified in the family, providing first-hand information about how
the gene influences heart development and function.
There were many
abnormalities that were identified and they included
- The cells began to beat weaker than
in normal heart cells.
- The mutation was also found to
affect the functioning of genes that were involved in the formation of the
heart, especially the ones that were involved in the development of the septum.
- The genes that were involved in the development of other
organs were turned on when they were supposed to be turned off. This highlights
the function of the GATA4 gene in activating and silencing other important
- The mutation in GATA4 prevented the activity of the
protein TBX5 from including genes for heart function and contraction. GATA4 and
TBX5 work together in activating and silencing genes that were involved in
heart function and development. A deficiency in one protein, affects the
functioning of the other protein as well. The mutation in TBX5 has also been
found to lead to the development of a hole in the septum.
While talking about the
far reaching effects of this study, Dr. Srivastava said,
"By studying the patients' heart cells in a dish, we were able to figure
out why their hearts were not pumping properly. Investigating their genetic
mutation revealed a whole network of genes that went awry, first causing septal
defects and then the heart muscle dysfunction."
This study supports the
previous studies conducted on the effect of GATA4 gene mutation and heart defects. In the study
conducted by Dr. Tomita Mitchell and colleagues titled GATA4 sequence variants in patients with congenital heart disease
it was found that GATA4 gene mutation was associated with a percentage of
septal defects in the heart and also among people with conotruncal defects.
In a study titled Congenital heart disease-causing Gata4
mutation displays functional deficits in vivo
, conducted by Misra C and
colleagues, it was found that mutation in the GATA4 gene affected cardiomyocyte
proliferation during embryogenesis that leads to congenital
The GATA4 protein is an
that influences the development of the heart and other organs
and, therefore, it cannot be directly targeted. There are downstream elements
to the protein which could be potential targets of therapy.
The studies conducted by
the scientists from Gladstone Institute of Cardiology identified a cluster of
genes that were involved in the development of the heart. The network of such
genes could be targets for therapy to lower the damages caused by the
mutation in GATA4 gene. The researchers claim that there are drugs that are
available and which can now be used to modify the downstream elements for congenital
heart disease patients.
- Congenital Heart Defects - (https:medlineplus.gov/congenitalheartdefects.html)
- Congenital heart disease-causing Gata4 mutation
displays functional deficits in vivo - (https:www.ncbi.nlm.nih.gov/pubmed/22589735)
- GATA4 sequence variants in patients with congenital
heart disease - (https:www.ncbi.nlm.nih.gov/pmc/articles/PMC2652815/)