“Today, understanding why Huntington’s disease progresses fast or slowly in different patients is mostly guesswork,” says lead author Dr. Christopher Pearson of The Hospital for Sick Children (SickKids). “Our research shows why this variation can occur in mice. If the findings are duplicated in humans, we could develop a new tool enabling genetic counselors to give more detailed information to families about the likely course of diseases such as Huntington’s disease, muscular dystrophy, and Friedreich’s ataxia,” he says.
Faulty repair gene
The job of the repair gene MSH3 is to fix broken DNA. However, for certain DNA sequences, like the one that causes Huntington’s disease and muscular dystrophy (myotonic dystrophy), the repair gene actually causes the mutation rather than repairs it.
Dr. Pearson’s international research team looked at the gene responsible for Huntington’s disease. They investigated the effect of two forms of naturally occurring variations of the repair gene upon the mutation in Huntington’s disease mice. The study shows that one form of the repair gene is associated with a faster mutation progression while another form is associated with slower mutation.
“Any repair tool can make a bad situation worse. A sledgehammer or a jeweller’s hammer will give different results, and it’s the same with some of our repair genes. Our research shows that the sledgehammer form of MSH3 causes more damage to DNA as compared to the jeweller’s hammer form. It worsens mutations like the one that causes Huntington’s disease or myotonic dystrophy,” Dr. Pearson explains. He is Senior Scientist in Genetics & Genome Biology at SickKids and is Associate Professor of Molecular Genetics at University of Toronto.
New tool for genetic counselling
Genetic counsellors would welcome an additional diagnostic tool when counselling families, says geneticist Dr. David Chitayat. “Many of the genetic neurological and neuromuscular disorders such as Huntingtons disease and myotonic dystrophy are devastating progressive disorders that result in death. However, the pace of the condition, currently, cannot be predicted. Informing the affected patients and their families about the likely course of the disease and the pace of progression would allow them to better plan their life and prepare for the worst. Finding a way to slow their progression would be a breakthrough in treating these disorders,” he says. Dr. Chitayat is Staff Geneticist at SickKids and Head of the Prenatal Diagnosis and Medical Genetics Program at Mount Sinai Hospital. He is a Professor of Paediatrics and Medical Director of the MSc Program in Genetic Counselling at University of Toronto.
Dr. Pearson adds that the research may have the potential to lead to a drug therapy targeting the DNA repair gene MSH3. If so, it would be the first (or among the first) effective treatment at the DNA level for Huntington’s disease. “We’ve got a lot of early-phase work to do, but it’s a direction that shows promise for the long term,” he says.
The genetic repair function is also important in Friedreich’s ataxia and at least 13 other neurodegenerative and neuromuscular diseases. Today’s research finding may be relevant as well to diseases of acquired genetic mutation, such as cancer, he adds.
This paper is titled “MSH3 Polymorphisms and Protein Levels Affect CAG Repeat Instability in Huntington’s Disease Mice,” published on-line in PLOS Genetics on February 28, 2013. SickKids authors are Drs. Christopher Pearson, Stéphanie Tomé, Jodie P. Simard, and Meghan M. Slean. International co-authors (from Toronto, Glasgow, and Albany, New York) are Drs. Kevin Manley, Greg W. Clark, Meera Swami, Peggy F. Shelbourne, Elisabeth R.M. Tillier, Darren G. Monckton, and Anne Messer.
Funders include the SickKids Foundation, Canadian Institutes of Health Research, Muscular Dystrophy Canada (Rachel Fund), the (US) National Institutes of Health, and generous support from Tribute Communities and the Kazman Family Fund.
About The Hospital for Sick Children
The Hospital for Sick Children (SickKids) is recognized as one of the world’s foremost paediatric health-care institutions and is Canada’s leading centre dedicated to advancing children’s health through the integration of patient care, research and education. Founded in 1875 and affiliated with the University of Toronto, SickKids is one of Canada’s most research-intensive hospitals and has generated discoveries that have helped children globally. Its mission is to provide the best in complex and specialized family-centred care; pioneer scientific and clinical advancements; share expertise; foster an academic environment that nurtures health-care professionals; and champion an accessible, comprehensive and sustainable child health system. SickKids is proud of its vision of Healthier Children. A Better World.™ For more information, please visit www.sickkids.ca.
About SickKids Centre for Research and Learning
The SickKids Centre for Research and Learning will bring together researchers from different scientific disciplines and a variety of clinical perspectives, to accelerate discoveries, new knowledge and their application to child health — a different concept from traditional research building designs. The facility will physically connect SickKids science, discovery and learning activities to its clinical operations. Designed by award-winning architects Diamond + Schmitt Inc. and HDR Inc. with a goal to achieve LEED® Gold Certification for sustainable design, the Centre will create an architectural landmark as the eastern gateway to Toronto’s Discovery District. The SickKids Centre for Research and Learning is funded by a grant from the Canada Foundation for Innovation, the Government of Ontario, philanthropist Peter Gilgan and community support for the ongoing fundraising campaign. For more information, please visit www.sickkidsfoundation.com/bepartofit.
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The Hospital for Sick Children