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Centre de recherche
Thursday, December 20 2018

Research connects gene defect to muscle and heart disease and identifies potential treatment

MONTRÉAL, December 20, 2018 – An international collaboration co-led by the CHU Sainte-Justine, the St. Michael’s Hospital in Toronto, the BC Children’s Hospital in Vancouver, and the Radboud University Medical Center in the Netherlands has identified that a rare disease gene called NPL (N-acetylneuraminate pyruvate lyase) is responsible for muscle and heart diseases. This work was published today in the prestigious journal, JCI Insight.

“This work was made possible through the collaboration of many experts from around the world,” said Dr. Xiao-Yan Wen, director of the Zebrafish Centre for Advanced Drug Discovery at St. Michael’s.

Dr. Clara van Karnebeek, a pediatrician and biochemical geneticist at BC Children’s Hospital, and her colleagues at the Centre for Molecular Medicine and Therapeutics of the University of British Columbia identified one family with heart disease and neuromuscular symptoms, as well as a marked increase in their sialic acid levels. Sialic acid is a sugar that helps cells to communicate with each other.

With a test called trio whole exome sequencing, which is used to identify the molecular basis of a genetic disorder, Dr. Maja Tarailo-Graovac identified mutations in the siblings’ NPL gene. Dr. Tarailo-Graovac is a researcher at the University of Calgary and an expert in high throughput sequencing approaches and their application for novel disease genes and genetic mechanism discoveries.

Since only one patient family with an NPL mutation was identified, the team searched for a match in various patient cohorts, and then went on to work with lab models to validate the effects of this very rare genetic mutation on a larger scale.

Dr. Wen, a world leader in zebrafish research, replicated the genetic make-up of the two siblings in the fish, and confirmed that an NPL gene deficiency in zebrafish resulted in muscle and heart problems, as it did in humans.

Importantly, his lab tested many disease treatment options by using various metabolites – molecules that are products of sialic acid metabolism - for NPL-deficient zebrafish. His team identified that specific sugar products formed from the NPL reaction – also known as monosaccharides ManNAc and GlcNAc – could potentially be used to treat this genetic disorder.

“First, this is a great discovery – no one had linked this gene to muscle myopathy before,” said Dr. Wen, who is also a scientist in Keenan Research Centre for Biomedical Science at St. Michael’s. “Second, it might mean better treatment options for NPL deficient patients down the road.”

Dr. Dirk Lefeber leads the Radboud Center of Expertise on Disorders of Glycosylation in the Netherlands and is an expert in sugar metabolism defects. His team studied the sugar metabolites in patient cells and found a clear reduction of the NPL products in red blood cells, while normal levels were found in skin cells.

“This showed the importance of sialic acid breakdown for human muscle physiology and pointed to the right sugars that could be used for therapeutic studies,” said Dr. Lefeber.

Dr. Alexey Pshezhetsky is a researcher at the CHU Sainte-Justine Research Centre and the Université de Montréal is an expert in sialic acid biology. His team established the effect of the identified mutations on the NPL enzyme. They are working on validating the results of this work in other lab animal models.

“Our preliminary data confirm that a mouse NPL deficient model also shows muscle weakness,” said Dr. Pshezhetsky.   

Dr. Wen, Dr. van Karnebeek, Dr. Lefeber, Dr. Tarailo-Graovac and others have previously shown that sialic acid synthesis by a different enzyme is important for brain and skeletal development. This work was published in Nature Genetics two years ago. Taken together, the team’s studies demonstrate the importance of the metabolism of sialic acid, a simple sugar compound, in human health and diseases.

“For these discoveries, teamwork involving different disciplines with the patients as partners is essential,” said Dr. van Karnebeek, who is now a researcher at the Amsterdam University Medical Center. “We need to continue this work and ensure it has an impact on our patients through improved outcomes, earlier diagnoses and identification of potential treatment targets.”

About the CHU Sainte-Justine Research Center

The Center is part of the CHU Sainte-Justine, the largest mother-child center in Canada and second largest pediatric center in North America. The CHU Sainte-Justine Research Center is a leading mother-child research institution affiliated with Université de Montréal. Focused on the discovery of innovative prevention methods, less intrusive and faster treatments and promising avenues for personalized medicine, it brings together more than 200 researchers, including more than 90 clinical researchers, as well as over 500 graduate and postdoctoral students. For more information, go to research.chusj.org.

CHU Sainte-Justine

Maude Hoffmann

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Updated on 2/12/2019
Created on 12/20/2018
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