Zebrafish help identify and understand new disease genes
by Dr. J. Verhagen (Erasmus MC)
In the Double Dose Consortium, researchers from various backgrounds collaborate to better understand how changes in DNA (mutations) can lead to cardiomyopathy in children and adults.
My research focuses on families where no hereditary predisposition has yet been identified.
Through new methods of reading DNA, we are learning more and more about the genetic causes of cardiomyopathy. More than a hundred genes have already been discovered that play a role in the heart muscle. Nevertheless, in about half of children with cardiomyopathy, no genetic cause can yet be demonstrated. This means there is still much to discover. Zebrafish can play an important role here.
A valuable animal model
Over the past decades, zebrafish have proven to be a valuable animal model in scientific research, particularly in the study of heart development and function.
What makes these fish so suitable for this type of research? They develop incredibly quickly: within 48 hours after fertilization, a beating heart is visible. This allows us to study changes in the heart over a short period. Moreover, the fish are transparent, enabling us to observe heart development under a microscope. Additionally, zebrafish are genetically very similar to humans: about 80% of human disease genes are the same. With genetic modification techniques, we can disable or modify specific genes to study their effects on heart development and function.
Figure A: Schematic representation of the zebrafish; the heart region is marked in red. Figure B: Anatomy of the zebrafish heart versus the human heart.
Sufficient evidence
“This approach was recently successfully applied in 3 children with dilated cardiomyopathy ( DCM ) and mutations in the FLII gene. This gene had not yet been linked to diseases in humans. Using CRISPR/Cas9 technology, we introduced the exact same mutations in zebrafish as found in the children. These zebrafish were then studied in detail.”
Zebrafish larvae with the same genetic predisposition as the children already showed features of cardiomyopathy at the age of 3 to 5 days.
“In this way, we were able to provide sufficient evidence that the mutations in the FLII gene are the cause of the cardiomyopathy in these children. The gene has now been added to the diagnostic gene panel. This means that this gene can now be examined in all children with unexplained cardiomyopathy…”
Zebrafish larvae undergo medication tests in the laboratory. The medications are added to the water in which the fish swim.
Changes at the protein level
Zebrafish, however, also serve another important function: they can help us learn more about the mechanisms involved in the onset of the disease by, for example, measuring changes at the protein level.
“Furthermore, we will use zebrafish in our follow-up research to test the effects of old and new medications. This will nicely complement the research on heart muscle cells taking place at Amsterdam UMC.”
Would you like to contribute to our scientific research, for instance by sharing ideas on new research goals and strategies? Please contact us via the Netherlands Cardiomyopathy Research Foundation.
Hartedroom (Dutch Foundation) funds the children’s portion of the scientific research project Double Dose. The research with zebrafish is funded by a personal Dekker Grant (03-003-2020T062) from the Dutch Heart Foundation.
Related Posts
Cardiac myosin inhibitors for HCM
The introduction of cardiac myosin inhibitors for HCM Hypertrophic cardiomyopathy ( HCM ) literally means: a thickened heart muscle disease. What is HCM all about? The heart is a hollow muscle that...
Surprising results from HCM study
New Research: How Does Metabolism Change in the Hearts of Patientswith Obstructive Hypertrophic Cardiomyopathy (oHCM)? Hypertrophic cardiomyopathy ( HCM ) is caused in many patients by hereditary...
