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RDMM Newsletter  |  Autumn 2016



Success at the Allied Genetics Conference

This July, Drs. Phil Hieter, Howard Lipshitz and Sanja Rogic of RDMM attended the Allied Genetics Conference, where the core focus was to promote communication among geneticists and develop collaboration across genetics research communities. Dr. Hieter, one of the conference co-chairs (and also former Genetics Society of America president), said the event was one of the first of its kind. “TAGC was a unique opportunity to bring together the various model organism communities in a 'jamboree' of seven individual meetings that included cross-cutting plenary sessions, joint poster sessions, and a variety of special events.  The result was spectacular - lots of interaction and exchange of ideas, great science, and a celebration of the power of model organisms in novel discovery and in drilling down into the detailed mechanisms of biological processes.” 

A series of blogs highlighting the meeting are on the GSA Genes to
Genomes blog.

Dr. Francis Collins, Director of the NIH

In the opening joint plenary session, Dr. Francis Collins, Director of the NIH, discussed the importance of model organism research in understanding the mechanisms of human health and disease, and the commitment by the NIH to continue to support fundamental research in model organisms.  A summary of his talk is available on the GSA website.

As one of the event’s sponsors, the RDMM logo was featured on the phylo card game given to all attendees (see article below).

Model Organisms Card Game
As one of the conference sponsors, RDMM contributed to the production of the model organisms card game. The deck was developed in collaboration with Genetics Society of America with the view to demonstrate the diversity of experimental techniques and organisms in the world of model organism research.
Sample decks were given to the research education programs at BCCHR and GenomeBC for use at their student events, as well as to the Vancouver-based Young Persons’ Advisory Group (YPAG). The YPAG took the game to the iCan Summit in Barcelona this summer where they engaged with other YPAGs from around the world.

Vancouver YPAG playing game at iCAN Summit in Barcelona


Clara van Karnebeek to Head the Division of Metabolic Diseases at Emma Children's Hospital

In January, RDMM Clinical Advisory Committee (CAC) member, Dr. Clara van Karnebeek, will begin an exciting new role as the head of the Division of Metabolic Diseases at Emma Children's Hospital, Academic Medical Centre in Amsterdam. The network is pleased she will be able to continue with the RDMM CAC remotely. As a member of the committee, Dr. van Karnebeek shares responsibility for setting and monitoring the clinical criteria to enable prioritization of the network’s projects, as well as conducting the first review of a clinical gene discovery proposal.
Dr. van Karnebeek has made tremendous contributions to the scientific understanding of rare genetic diseases through her work as an investigator at BC Children’s Hospital, and some of her recent successes have been noted in the
 spring and summer RDMM newsletters.  
Rare Disease NCE Planning Workshop
The next call for Canadian Networks of Centres of Excellence (NCE) is anticipated in spring 2017, and in response a team of leading rare disease investigators are meeting to plan a submission for a collaborative and patient-centred NCE that will harmonize and improve the diagnosis and care of patients with rare diseases. Both RDMM and MICYRN are proposed partners in the initiative. Attendees at the workshop, which is planned later this month during the
ASHG conference, will work on developing the NCE framework, which includes pillars, themes, exemplar projects, platforms, partners, and cross-cutting initiatives. Stay tuned for future updates. 

Reminder: Clinicians studying rare disease genes should submit an application if they haven't already done so. There are still opportunities to be matched with a researcher working on the same gene.

Please forward to colleagues who may be interested in applying for a catalyst grant.

Collaboration between RDMM and the U.S. Model Organism Screening Center (MOSC) of the Undiagnosed Disease Network (UDN)

The Model Organism Screening Center (MOSC), a three-year project funded by the National Institutes of Health, is led by Hugo Bellen from the Baylor College of Medicine (BCM) and is comprised of drosophila and zebrafish labs at the BCM and the University of Oregon. The center will evaluate the pathogenicity and function of approximately 200 gene variants per year identified through the Undiagnosed Diseases Network (UDN). 
Earlier this month, the RDMM and MOSC established a collaboration to promote the interaction between Canadian model organism researchers and the MOSC to exchange information and reagents to model diseases and study the basic biology. The collaboration will also benefit rare disease gene discovery by cross-referencing the list of symptoms and associated candidate genes identified in the two projects with one another to identify patients with similar variants and conditions. 
Canadian researchers and researchers from the MOSC working on related genes have started conversations on working together.  Stay tuned for more details on these newly formed collaborations.

Catalyst Grant Recipient Update

A number of teams awarded catalyst grants have made significant progress in their studies over the last few months. Each issue of the RDMM newsletter will highlight some of this work.   

Insights into New Treatment for Childhood Onset Neurological Disease
Micheil Innes (University of Calgary) followed a five-year old girl with progressive stiffness and spasticity in the lower limbs, learning problems and hearing loss. Through whole-exome sequencing, he identified that the patient had a homozygous missense variant in a novel candidate gene. Recent studies by another team from Sweden reported a different homozygous missense variant in the same candidate gene in a patient with weakness, hearing loss and neuropathy, making the link between this gene and recessive neurological disease even more plausible.
Dr. Innes will be collaborating with Siegfried Hekimi (McGill University), who through years of model system work on this candidate gene has developed evidence that treatment with a compound (2,4-DHB) could bypass the metabolic block. Dr. Hekimi has been using his mouse model and carry out biochemical and molecular analyses to characterize the gene mutation. The enzyme encoded by the candidate gene is necessary for the biosynthesis of ubiquinone (co-enzyme Q; UQ), and the intermediate demethoxyubiquinone (DMQ), which accumulates in its absence.
To date, Dr. Hekimi’s laboratory has obtained clear results on the molecular analysis of the gene mutations. They performed work on both the mouse model and fibroblasts from Dr. Innes’ patient and a Swedish patient.  Their study revealed the two hallmarks expected from the loss of the candidate gene: a 30% decrease in UQ level compared to a normal control, and an accumulation DMQ.
Treatment of the patient cells with 2,4-DHB did not result in an increase of UQ level, but completely abolished the accumulation of DMQ, indicating a two-fold effect. The first effect is production of UQ without using the gene, and secondly, an inhibition of the native UQ biosynthetic pathway. The latter can significantly offset the increase of UQ production due to the alternative pathway using 2,4-DHB if the native pathway in the patient cells is still largely functional. Treatment with 2,4-DHB as well as exogenous UQ10 resulted in a small but significant increase of the maximal mitochondrial respiration rates.  The skin fibroblast cells from the Swedish patient have a more severe UQ deficiency. Treating the cells with 2,4-DHB increased their UQ production, which was accompanied by less accumulation of DMQ. The improvement in mitochondrial function was also much more dramatic in these cells after treatment with 2,4-DHB or exogenous UQ. Because of the inhibition of the native pathway, additional future work will be necessary to determine how severe a patient’s UQ deficiency has to be to warrant treatment with 2,4-DHB.

Hekimi Lab (Project lead Dr. Ying Wang, front row, far right)

Work on Genetic Cause of HHT Leading to Improved Analysis Techniques

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disease characterized by development of telangiectasia and arteriovenous malformations (AVM) in the brain, lung and other viscera. This can lead to hemorrhage, stroke and other life-threatening complications; about 20% of all cases have an unknown genetic cause. 
Through whole exome sequencing, Hanna Faghfoury (University of Toronto, Mount Sinai Hospital/University Health Network) and colleagues identified an HHT family with no known HHT gene mutations.  An identified gene inhibits vascular endothelial growth factor (VEGF)-evoked MAP kinase (MAPK) in endothelial cells (ECs) making it a compelling candidate gene. Dr. Faghfoury will be working with Kathy Siminovitch (Mount Sinai Hospital/University Health Network) to generate a CRISPR-based gene knock-in mouse model to define the mechanisms whereby the mutant gene protein alters EC biology causing HHT. Results to date confirm their hypothesis that this mutation has a dominant‐negative effect on gene function.
The team also started collaborating with Phil Marsden (University of Toronto) who is providing primary ECs that have very high proliferative potential. CRISPR/Cas editing is being repeated in these cells together with the use of a quantitative reporter system to more precisely delineate the effects of the mutant protein on EC biology.
Dr. Siminovitch’s lab is now investigating the specific effector pathways whereby TGFβ signaling is altered in these cells in order to determine mechanisms in the mutant protein that compromise TGFβ signaling. Dr. Siminovitch is collaborating with Alan Peterson (McGill University) to accelerate the development of the disease gene‐expressing mutant mice. The work will provide them with new knowledge of the candidate gene’s roles in ECs, as well as expertise in technologies that can then be applied to analysis of the mutant mice.

In the coming months, Dr. Siminovitch will be developing a new screening approach that exploits the single cell analytic platform developed by Fluidigm.  This strategy will allow them to perform whole‐transcriptome analyses on single ECs and to avoid the need for long‐term passaging of primary, genome‐edited cells. For this work, Fluidigm is providing reagents to help develop this novel application for their single cell analysis platform.

Ben Pinder, postdoctoral fellow in the Siminovitch lab


A New Call for Dravet Spectrum Disorder Proposals

Last year, RDMM and teamed up on a successful call for proposals that use a model organism approach to investigate disease pathogenesis to inform therapeutic strategies related specifically to Dravet Spectrum (DS) Disorder. This March, an award of $25,000 was given to Drs. Pierre Drapeau and Éric Samarut (Research Center of the University of Montreal Hospital Center) in which they propose to use zebrafish to characterize the phenotype of novel DS-causing genes and to screen for potent small molecules that could rescue their DS-like condition.
The RDMM and are holding another open call for proposals this year. The submission deadline is December 15 for a $25,000 grant awarded over one year. Applications may be submitted by any investigator associated with a Canadian Institution. For more information visit the
RDMM website.

Global Alliance for Genomics and Health 4th Plenary Meeting

The 4th Plenary Meeting of the Global Alliance for Genomics and Health will bring together (GA4GH) meeting will be taking place on October 16-18 in Vancouver, bringing together its international membership. The focus of the meeting will be on facilitating rapid uptake of GA4GH tools and solutions in real-world settings.

More information is available on the event website for those attending.
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