Funding outcome

The purpose of this line of research is to understand why a young girl, who presented to the Stollery Children's Hospital several years ago, has low levels of calcium in her blood. The principal applicant is a pediatric nephrologist who has particpated in her care. Her clinical picture was consistent with a rare diagnosis called 'Autosomal Dominant Hypocalcemia', i.e. low calcium levels in the blood. However, genetic testing for the known causes of this disorder was repeatedly negative. Consequently, through a research protocol the applicant acquired her and her families DNA (Mom, Dad and sibling). All four family members had their genomes sequenced, and then compared looking for a change in the affected child's DNA that was absent in the others. In so doing, the applicant identifed a change (likely a mutation) that we propose causes her disease. The affected gene has not been reported to cause this disease to date. However, mutations in this gene cause other disorders that have low blood calcium levels as one part but are more severe and also include changes in the skeleton leading at times to death as an infant. This proposal seeks to understand how mutations in this gene causes decreased blood calcium levels. To do so we will use cell models and introduce the gene in its normal form or with the disease causing mutations and then assess the abiltiy for the cell to sense changes in calcium. We believe that the mutations in this gene make the cell overly sensitive to calcium, fooling the body into believing that blood calcium levels are normal (when in fact they are low) and thus the body fails to respond appropriately to increase blood calcium levels. Ultimately this work will hopefully provide an answer as to why this child has low blood calcium levels, and why other children with mutations in this gene have low blood calcium levels. Perhaps more improtantly, this information will provide more general information on how we regulate blood calcium levels and suggest ways that we can manipulate blood calcium levels to our advantage clinically, i.e. in the treatment of these children or other people with disorders of calcium homeostasis such as kidney stone formers or women with osteopenia.