91社区

Mutations in a gene involved in brain development have led to the discovery of two new neurodevelopmental diseases by an international team led by researchers at 91社区 and CHU Sainte-Justine Research Center.

The first clues about the rare disorder arose after doctors were unable to diagnose why two siblings from Qu茅bec City were experiencing seizures and neurodevelopmental deficits. Desperate, the children鈥檚 family turned to Carl Ernst at the Douglas Mental Health University Institute in Montreal for answers.

Ernst, who is also a professor in 91社区鈥檚 Department of Psychiatry, and his team used harvested skin cells from the toddlers and 鈥渞eprogrammed鈥� them to assume a stem cell-like state鈥攊nduced pluripotent stem cells (iPSC). By making neurons from the iPSCs and comparing them to those of healthy individuals, the researchers found that they did not develop properly. Upon further investigation, they discovered a potential culprit: the family carried a mutation in ACTL6B 鈥� an epigenetic regulator implicated in neuronal development.

Around the same time, Dr. Philippe Campeau, a medical geneticist from CHU Sainte-Justine Research Center, was also studying ACTL6B mutations identified in two families as part of an epilepsy genome study led by his colleagues Dr. Jacques Michaud and Dr. Elsa Rossignol. With the help of Julie Lessard, an ACTL6B expert from the Institute for Research in Immunology and Cancer, Dr. Campeau was mapping how ACTL6B mutations affected protein interactions. After hearing a lecture given by Professor Ernst about his work on ACTL6B, Campeau, who is also a professor at Universit茅 de Montr茅al, realized they were working on the same mutations so the researchers decided to join forces to study this disease.

By reaching out to peers in over 10 countries, they soon found similar isolated cases throughout the world.

鈥淭hat鈥檚 when we knew that we were looking at a newly identified genetic disease,鈥� says Scott Bell, a PhD student in the Ernst lab and lead author of a new study in the American Journal of Human Genetics detailing the findings.

As they identified patients with mutations in ACTL6B, the researchers noticed they segregated into two different groups. The first鈥攚hich had recessive mutations (both copies of the gene are affected) in 础颁罢尝6叠鈥�suffered from epilepsy and neurodevelopmental problems. The second group鈥攖hat only had one copy of the gene with mutations鈥攁lso had problems with neurodevelopment but did not experience seizures. They also showed language delays and hand stereotypies seen in Rett syndrome (caused by mutations in another epigenetic regulator).

鈥淭his was very surprising,鈥� says Justine Rousseau, Dr. Campeau鈥檚 research associate who conducted the protein interaction studies. 鈥淚t provides very strong evidence that there are in fact two separate neurological genetic diseases caused by mutations in the same gene, ACTL6B.鈥�

Thanks to new research tools such as iPSC and CRISPR gene editing technology, the study showed that ACTL6B mutations caused a dysregulation of other genes important for the development of dendrites, branched projections of neurons that play a critical for communication between brain cells.

Ernst says that their work is concrete proof that new technology is making it easier for scientists to study both rare and neurodevelopmental diseases.

鈥淲e鈥檙e very happy about this work because concerned families with this disease have, for the first time, a means to understand the problems affecting them,鈥� Ernst says. 鈥淭he tools we used also provide further evidence of the crucial role ACTL6B plays in brain development and this needs to be further investigated.鈥�

This study was funded by the Fonds de recherche en sant茅 du Qu茅bec, the Government of Indonesia, the Mexican National Council of Science and Technology, MITACS, Genome Canada and G茅nome Qu茅bec, AMED, MEXT, JST, MHLW, the Takeda Science Foundation and the Canadian Institutes of Health Research.

鈥淢utations in ACTL6B cause neurodevelopmental deficits and epilepsy and lead to loss of dendrites in human neurons,鈥� by Scott Bell et al., was published in the American Journal of Human Genetics.

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About the CHU Sainte-Justine Research Center
CHU Sainte-Justine Research Center is a leading mother-child research institution affiliated with Universit茅 de Montr茅al. It brings together more than 200 research investigators, including over 90 clinician-scientists, as well as 500 graduate and postgraduate students focused on finding innovative prevention means, faster and less invasive treatments, as well as personalized approaches to medicine. The Center is part of CHU Sainte-Justine, which is the largest mother-child center in Canada and second pediatric center in North America. More on

脌 propos du Centre de recherche du CHU Sainte-Justine
Le Centre de recherche du CHU Sainte-Justine est un 茅tablissement phare en recherche m猫re-enfant affili茅 脿 l鈥橴niversit茅 de Montr茅al. Ax茅 sur la d茅couverte de moyens de pr茅vention innovants, de traitements moins intrusifs et plus rapides et d鈥檃venues prometteuses de m茅decine personnalis茅e, il r茅unit plus de 200 chercheurs, dont plus de 90 chercheurs cliniciens, ainsi que 500 茅tudiants de cycles sup茅rieurs et postdoctorants. Le centre est partie int茅grante du Centre hospitalier universitaire Sainte-Justine, le plus grand centre m猫re-enfant au Canada et le deuxi猫me centre p茅diatrique en importance en Am茅rique du Nord. D茅tails au

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Contact:

Justin Dupuis
Media Relations
91社区
Tel.: 514 398-6751
justin.dupuis [at] mcgill.ca
http://www.mcgill.ca/newsroom/

Florence Meney
Conseill猫re cadre - Relations m茅dias
CHU Sainte-Justine
Tel.: 514 755-2516
florence.meney.hsj [at] ssss.gouv.qc.ca

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