September 20, 2001
Researchers create mouse model for human congenital heart disease
Researchers at The Hospital for Sick Children, Harvard Medical School and the Clinical Research Institute of Montreal have created the first mouse model relevant to the study of congenital heart disease in humans. The mouse model will allow for further research into the genetic causes of congenital heart disease, as well as providing a living model to test possible new treatments. This research is reported in the cover article of the September 21 issue of the scientific journal Cell.
While a postdoctoral fellow in the laboratory of Drs. Jonathan and Christine Seidman at Harvard Medical School, Dr. Benoit Bruneau, now a scientist in The Hospital for Sick Children Research Institute, developed the mouse model for Holt-Oram syndrome. The characteristics of Holt-Oram syndrome, a rare inherited disease caused by a mutation in one of the Tbx5 genes, were reproduced in mice. Infants with Holt-Oram Syndrome have upper limb abnormalities, and often have heart abnormalities that may include structural malformations of the heart and/or abnormal transmission of electrical impulses that coordinate the heart's muscular contractions (conduction defects). The structural defects in Holt-Oram are usually septal defects, or "holes in the heart," the most common type of congenital heart defect found in children.
"Tbx5 is a transcription factor, a regulatory gene that turns off and on other genes, which is known to cause Holt-Oram syndrome and is believed to control many aspects of cardiac development," said Dr. Bruneau, the study's lead author, a scientist at The Hospital for Sick Children, and assistant professor of Molecular and Medical Genetics at the University of Toronto. "Already through research with this mouse model, we have identified for the first time that certain genes are very sensitive to Tbx5 levels, and at least one of these is probably at the root of the conduction defects in Holt-Oram syndrome."
"Transcription factor gene mutations appear to play a critical role in several forms of congenital heart disease," said Dr. Jonathan Seidman, one of the study's senior authors, professor of Genetics at Harvard Medical School and an investigator at the Howard Hughes Medical Institute. "This model will be useful for further investigating the genetic causes of not only Holt-Oram syndrome, but we suspect, of other congenital heart disease."
The Seidman laboratory collaborated with Dr. Mona Nemer, director of Cardiac Growth and Differentiation Research at the Clinical Research Institute of Montreal and one of the study's senior authors. Dr. Nemer's lab identified the biochemical mechanism for what had been observed in the mouse model - that the gene abnormalities thought to cause the conduction defects were a direct result of decreased doses of the Tbx5 protein. They also identified that Tbx5 works in conjunction with another transcription factor (Nkx2-5) to regulate cardiac genes.
"The fact that Tbx5 and Nkx2-5 interact together to regulate similar genes explains how mutations in different genes cause the same heart problem. This paves the way to a better understanding of the molecular basis of inherited heart disease," explained Dr. Nemer, who holds a Canada Research Chair in Molecular Biology and is professor of Pharmacology and Medicine at University de Montréal and McGill University.
Congenital heart defects are among the most prevalent and serious diseases affecting children, with an incidence of up to one in a hundred live births. Septal defects are found in 2.5 per 1,000 live births.
"The focus of my research now is to investigate what genes Tbx5 regulates, and which of these may be causing congenital heart defects. We hope these studies will eventually provide us with potentially improved diagnostic tools, as well as targets for new therapies for congenital heart disease," added Dr. Bruneau, who holds a Heart and Stroke Foundation of Canada/Canadian Institutes of Health Research New Investigator Award.
This research was supported by the American Heart Association, the Canadian Institutes of Health Research, the Howard Hughes Medical Institute, the National Cancer Institute of Canada, and the National Institutes of Health.
The Hospital for Sick Children is a health care, teaching and research centre dedicated exclusively to children; affiliated with the University of Toronto. For more information, please visit www.sickkids.ca.
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