Celebrating the impact of health research

When too much is definitely too much: genetic mutation prevents vitamin D breakdown

Glenville Jones
Department of Biomedical and Molecular Sciences, Queen's University


In post–WWII Britain, there was an "epidemic" of a disease called idiopathic infantile hypercalcemia (IIH), which causes the build–up of calcium in the kidneys. The rising incidence of the condition was blamed upon excessive vitamin D fortification and caused the government at the time to abruptly stop vitamin D fortification practices. The incidence of IIH fell marginally after the end of such fortification, but the disease continues to be reported all over the world, including Canada.

Recently, two German pediatric nephrologists, Martin Konrad and Karl–Peter Schlingmann, and I showed that one of the main causes of IIH is loss–of–function genetic mutations of CYP24A1, the enzyme responsible for the breakdown of vitamin D. Loss of CYP24A1 function results in too much vitamin D and, since vitamin D is one of the main players in maintaining blood calcium levels, excessive blood calcium. This, in turn, causes damage to the kidney, kidney stones and soft tissue calcification.

Basic science the foundation for clinical application

I have been studying CYP24A1 for the past two decades, with my work showing its exact role in a breakdown pathway for the major forms of vitamin D. In 1996, with the help of Parteq, the patient and commercialization office at Queen's University, and in partnership with Dr. Martin Petkovich, I co–founded a start–up biotechnology company, Cytochroma Inc. which went on to develop CYP24A1–inhibitors. These drugs are now in Phase 2 clinical trials. In addition, working with Dr. Rene St–Arnaud of the Shriner's Hospital in Montreal, and using a "knockout" mouse, bred to have the loss–of–function mutation of CYP24A1, we have shown that the enzyme seems to be the only route for vitamin D excretion; thus, the genetic defect leaves the animal susceptible to vitamin D toxicity.

Our focus was on basic science to gain a better understanding of CYP24A1. But our German colleagues contacted us because they'd found genetic changes to the enzyme in patients with IIH. They wanted to know – and so did we! – whether these were simply genetic variants, known as polymorphisms, or were they loss–of–function mutations.

Thanks to our previous work and our development of a computer model for human CYP24A1, we were able to discern fairly quickly that the changes in CYP24A1 in babies with IIH were probably loss–of–function mutations. Nonetheless, we recreated most of the genetic changes found in the patients in the cultured cell model and showed that, in all cases, the mutation wiped out enzyme activity. It was indisputable evidence – CYP24A1 mutations cause IIH.

Without these CIHR–supported basic science tools, the task of proving the role of CYP24A1 would have been much tougher. In other words, our basic science groundwork and engineered tools set the stage for the clinical breakthrough. We started out not knowing the full importance of CYP24A1 – but this discovery fully justified the many years we have spent studying its basic science aspects.


Our work was published as a landmark study in the New England Journal of Medicine in August 2011 and has already resulted in several reports, particularly in American journals, confirming that mutations of CYP24A1 cause hypercalcemia not just in children but in adults too. Indeed, patients identified as adults frequently have kidney stones and thus our work has spawned studies of the frequency of CYP24A1 mutations in patients with such stones. In fact, from recent estimates of the frequency of CYP24A1 polymorphisms and mutations in the population (one in 120), this may turn out to be a significant cause of kidney stones.

Our work has also led to streamlined methods for the diagnosis of CYP24A1–related disease, with improved mass spectrometry–based methods to detect the 24–hydroxylated metabolites of vitamin D that are absent in IIH patients. Armed with these new tools, Celia Rodd (McGill and Montreal Children's Hospital) and I have initiated a program to test all the estimated 600 Canadian IIH patients identified in pediatric centres across Canada. This is one of those clear examples of bench to the bedside – and back to bench – research. We believe that our research will eventually help in diagnosing, managing and treating all hypercalcemic patients throughout the world.


Collaborators: Karl–Peter Schlingmann and Martin Konrad, Children's Hospital Muenster/University of Muenster; Rene St–Arnaud, Shriner's Hospital/McGill University; Celia Rodd, Montreal Children's Hospital/McGill University; Dr. Charles Bishop, CEO, Cytochroma Inc, Markham ON

Funding: Canadian Institutes of Health Research (CIHR) multiple operating and university–industry grants; Cytochroma IncResearch Impact, Markham ON


Schlingmann, K.P., Kaufmann, M., Weber, S., Irwin, A., Goos, C., John, U., Misselwitz, J., Klaus, G., Kuwertz–Broking, E., Fehrenbach, H., Wingen, A.M., Guran, T., Hoenderop, J.G., Bindels, R.J., Prosser, D.E., Jones, G., Konrad, M. (2011). Mutations of CYP24A1 and Idiopathic Infantile Hypercalcemia. New Engl J Med, 365, 410–421 [Epub June 15 2011 ahead of print].

Jones, G., Kaufmann, M., Prosser, D. (2012). 25–hydroxyvitamin D3–24–hydroxylase (CYP24A1): Its important role in the degradation of vitamin D. Arch Biochem Biophys, 523, 9 –18. In Special Issue on Vitamin D. Eds: DeLuca HF, Plum LA. [Epub Nov 12 2011 ahead of print].

Lights! Camera! Action! Action schools! BC promoting healthy living in BC schools

Heather A. McKay
Department of Orthopaedics and Department of Family Practice, University of British Columbia
Centre for Hip Health and Mobility, Vancouver Coastal Health Research Institute

Heather M. Macdonald
Department of Orthopaedics and Department of Family Practice, University of British Columbia
Centre for Hip Health and Mobility, Vancouver Coastal Health Research Institute
Child & Family Research Institute, Vancouver, BC

Lindsay Nettlefold
Department of Orthopaedics, University of British Columbia
Centre for Hip Health and Mobility, Vancouver Coastal Health Research Institute

Bryna Kopelow
JW Sporta, Richmond, BC

Jennifer Fenton
JW Sporta, Richmond, BC

Patti–Jean Naylor
School of Exercise Science, Physical and Health Education, University of Victoria


There is a crisis in children's health. Current statistics indicate that only 7% of Canadian children and youth achieve recommended levels of daily physical activity.1 In addition, Canadian children and youth spend close to 9 hours/day in sedentary pursuits1 and more than 75% of youth aged 2–17 years do not consume the recommended 5 or more servings of fruits and vegetables.2 These poor activity and eating habits are leading to declines in cardiovascular fitness and high rates of overweight, obesity and type 2 diabetes among Canadian children and youth.3, 4 This crisis is a major public health concern that threatens to substantially increase the burden of chronic disease in Canada. There is a need for effective and sustainable solutions to promote healthy living among children and youth. As children spend the majority of their waking hours in school and schools reach a diverse population, schools are often the venue of choice to implement health promotion programs.5 However, few school–based programs have proven effective or sustainable.

The Action Schools! BC (AS! BC) is an exception to that rule. AS! BC, developed in 2002, is a best practices model designed to help elementary schools create individualized action plans to promote healthy living while achieving academic outcomes. AS! BC promotes the creation of inclusive and diverse daily physical activity and healthy eating opportunities and supports schools in making healthy choices the easy choices for students, teachers, administrators and other members of the school community. Our vision is that healthy living will be integrated into the fabric of BC schools and maintained through partnerships with families and communities.

Evaluation supports expansion

In 2003, shortly after the program began operation, we set out to evaluate the efficacy of AS! BC for increasing physical activity and improving a variety of health outcomes in elementary school children and to do so in a rigorous manner. First, the AS! BC Support Team developed practical and relevant professional–development, curriculum–linked resources (teaching resources and support materials) that supported a Comprehensive School Health approach and contributed to specific health and academic outcomes. Many of these resources were included in the AS! BC Classroom Action Bin, which we provided to teachers in participating schools. Second, our Evaluation Team conducted a randomized controlled trial that involved 10 elementary schools in Vancouver and Richmond, BC (seven intervention and three usual practice). From these 10 schools, more than 500 grade 4–6 students volunteered to participate in our comprehensive, evidence–based health outcome evaluation that spanned one–and–a–half school years.

We found that, through promotion of physical activity across six Action Zones, AS! BC had a significant positive influence on the number of minutes of physical activity provided to students.6 This included an additional 15 minutes/day of physical activity delivered within the Classroom Action Zone and incorporated a simple high–impact jumping program, Bounce at the Bell. Due to the increase in physical activity, children in the intervention schools had significantly greater gains in bone mass and strength7, 8, 9 and improvements in cardiovascular fitness and blood pressure.10 They also showed increased awareness of dietary requirements compared with children in usual–practice schools. Further, despite the 15–minute reduction in time devoted to the regular curriculum, children in intervention schools maintained a level of academic performance similar to that of children in usual–practice schools.11 Results of focus groups showed teachers, parents and students were highly satisfied with the AS! BC model and its resources.12

These positive findings had a significant impact on school health in BC by providing a foundation for the scale–up of AS! BC and the development of additional modules and school health policies. Specifically, in 2004, we received financial support from the BC Ministry of Health to roll out AS! BC across the province and, in 2005, we developed K–to–3 and middle–school components. This was followed by a student leadership component in 2006 and a province–wide healthy–eating component in 2007. AS! BC contributed to the implementation of Daily Physical Activity for children in kindergarten through Grade 7 and Guidelines for Food and Beverage Sales in BC schools.

Over 2005–07, we evaluated AS! BC as disseminated more broadly to schools across four BC provincial health authorities. Although teachers in this trial had substantially less interaction with the AS! BC Support Team than in our efficacy trial, we noted a 38–42% increase in cardiovascular fitness (adjusted percent change) over year one in children attending intervention schools.

The 2011–12 school year marked Year 8 of the provincial roll–out for AS! BC; as of June 30, 2012, 1,455 (92%) of BC schools were registered with the program. Participation in AS! BC workshops delivered by the Support Team has far exceeded expectations, with 86% of BC schools, representing more than 62,000 teachers, administrators and other key stakeholders, having participated in one or more workshops since 2004. The significant uptake confirms the value and relevance of the AS! BC framework for action, and the support services and resources available. Further, the scale up of AS! BC has provided the foundation for leading–edge research on implementation of school health frameworks. Continued efforts are needed to continue to engage schools across the province, and support implementation and sustained action to contribute to the health of BC children.


Partnerships were integral to the success of AS! BC to date, and continue to pave the way forward. National and international partnerships enhance AS! BC by providing connections with broader social movements promoting healthy living, enabling collection of new best practices and interventions, and connecting the Support Team with other organizations committed to promoting healthy schools.

Across Canada, informal agreements or collaborations are in place with Yukon and Nova Scotia; information and resources are shared informally with Alberta, Saskatchewan, Manitoba, New Brunswick, Newfoundland and Labrador, and Nunavut. Alberta's Ever Active Schools Program adopted the AS! BC Classroom Action bin model, and integration of AS! BC teaching resources and support materials into the Alberta Project Promoting Active Living and Healthy Eating (APPLE Schools) is being discussed. In Saskatchewan, the in motion program sent delegates for training, purchased Classroom Action bins, and created a school program with elements adapted from AS! BC. In addition, with support from Health Canada's Aboriginal Diabetes Initiative, AS! BC training, support materials and teaching resources were provided to target Saskatchewan schools in collaboration with the Yorkton Tribal Council and the Prince Albert Grand Council.

Internationally, the AS! BC Evaluation and Support Teams communicated with researchers and practitioners in South Africa who have incorporated the whole school framework and technical support services based on the consultation. AS! BC also received recognition from the Irish parliament, organizers of the 2014 Commonwealth Games and from the President of the Norwegian Physical Activity and Nutrition Council.

Moving forward, the AS! BC Support Team will continue to support new and existing Action Schools, and build on established partnerships with other organizations committed to improving the health of Canadian youth. These efforts will ensure that AS! BC continues to provide more opportunities for more children to make healthy living choices more often.


We gratefully acknowledge the school administrators, teachers, parents and children in Action Schools! BC schools for their support and participation in the initial evaluation study, and for contributing to the success of Action Schools! BC.

Individuals, communities/cities/ regions and organizations involved: University of British Columbia, University of Victoria, JW Sporta, Province of British Columbia (Ministry of Health, Ministry of Education), 2010 Legacies Now, Directorate of Agencies for School Health (DASH BC)

Funding: We are grateful for the support from the Canadian Institutes of Health Research (CIHR) for the provincial dissemination of Action Schools! BC.


Footnote 1

Colley, R.C., Garriguet, D., Janssen, I., Craig, C.L., Clarke, J., Tremblay, M.S. (2011). Physical activity of Canadian children and youth: accelerometer results from the 2007 to 2009 Canadian Health Measures Survey. Health Rep, 22, 15–23.


Footnote 2

Tjepkema, M., Shields, M.. (2005). Nutrition: Findings from the Canadian Community Health Survey – Overweight Canadian children and adolescents. Statistics Canada Catalogue no. 82–620– XWE2005001.


Footnote 3

Shields, M. (2006). Overweight and obesity among children and youth. Health Rep,17, 27 –42.


Footnote 4

Ball, G.D., McCargar, L.J. (2003). Childhood obesity in Canada: a review of prevalence estimates and risk factors for cardiovascular diseases and type 2 diabetes. Can. J. Appl. Physiol, 28, 117 –140.


Footnote 5

Fox, K.R., Cooper, A., McKenna, J. (2004). The school and promotion of children's health–enhancing physical activity: Perspectives from the United Kingdom. J. Sch. Health, 23, 338 –358.


Footnote 6

Naylor, P.J., Macdonald, H.M., Warburton, D.E., Reed, K.E., McKay, H.A. (2008). An active school model to promote physical activity in elementary schools: Action Schools! BC. Br. J. Sports Med, 42, 338–343.


Footnote 7

Macdonald, H.M., Cooper, D.M., McKay, H.A. (2009). Anterior–posterior bending strength at the tibial shaft increases with physical activity in boys: evidence for non–uniform geometric adaptation. Osteoporos. Int, 20, 61–70.


Footnote 8

Macdonald H.M., Kontulainen S.A., Khan K.M., McKay H.A. Is a school–based physical activity intervention effective for increasing tibial bone strength in boys and girls? J. Bone Miner. Res. 2007; 22:434–446.


Footnote 9

Macdonald, H.M., Kontulainen, S.A., Petit, M.A., Beck, T.J., Khan, K.M., McKay, H.A. (2008). Does a novel school–based physical activity model benefit femoral neck bone strength in pre– and early pubertal children? Osteoporos. Int, 19, 1445–1456.


Footnote 10

Reed, K.E., Warburton, D.E., Macdonald, H.M., Naylor, P.J., McKay, H.A. (2008). Action Schools! BC: a school–based physical activity intervention designed to decrease cardiovascular disease risk factors in children. Prev. Med, 46, 525 –531.


Footnote 11

Ahamed, Y., Macdonald, H., Reed, K., Naylor, P.J., Liu–Ambrose, T., McKay, H. (2007). School–based physical activity does not compromise children's academic performance. Med. Sci. Sports Exerc, 39, 371 –376.


Footnote 12

Naylor, P., Macdonald, H.M., Reed, K.E., McKay, H.A. (2006). Action Schools! BC: A socio–ecological approach to modifying chronic disease risk factors in elementary school children. Prev Chronic Dis [serial online] Available at: Centers for Disease Control and Prevention. Accessed May 20, 2006.


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