Asra Almubarak Faculty of Medicine & Dentistry

Diving deep into DNA to help a child with hereditary rickets

A researcher investigates gene mutations implicated in a case of rickets to pinpoint the cause

Childhood diseases such as rickets often impact not just the child, but also the family and community. Rickets, the softening and weakening of bones in children, is caused by either dietary deficiency or genetic abnormalities and affects around one in 200,000 children.

Hereditary hypophosphatemic rickets (HHR) can result from mutations in several genes and is a disorder related to low levels of phosphate – a mineral that is crucial for bone development and strength – in the blood. Phosphate levels are largely controlled by the kidneys, which normally excrete excess phosphate in urine, and also reabsorb it into the bloodstream when more is needed.

X-linked hypophosphatemic rickets, the most common form of HHR, is caused by mutations in the PHEX gene, which provides instructions for making an enzyme that is active primarily in bones and teeth. PHEX can regulate fibroblast growth factor 23 (FGF23), a hormone produced in bone cells that manages the body's phosphate levels. Gene mutations increase the production or reduce the breakdown of FGF23 which affects phosphate levels in the bone.

Asra Almubarak, a WCHRI postdoctoral fellow in the Department of Pediatrics, is diving deep into DNA to investigate the role of SVEP1, a protein coding gene, in bone mineral balance.

“A nine year old with the signs and symptoms of hereditary hypophosphatemic rickets was identified, however, she lacked mutations in any of the genes like PHEX, which are known for causing this disorder,” explains Almubarak, who is supervised by Stollery Science Lab Distinguished Researcher Todd Alexander.

After sequencing the DNA of the girl, as well as those of her parents, the Alexander lab identified nine new gene mutations, but only one in a gene expressed in bones – SVEP1.

“We think that SVEP1 regulates FGF23 production or secretion from bone cells, affecting phosphate levels” says Almubarak. “Through this research we hope to understand how the idedntified mutation in SVEP1 increases FGF23 release and thus decreases phosphate levels in the blood, leading to rickets..”

The research team will manipulate SVEP1 in zebrafish and cell models to test whether this is the cause of disease.

Almubarak explains that there are limited treatment options for most cases of HHR.

“I hope my research facilitates the discovery of a safe and effective treatment for children with hereditary hypophosphatemic rickets, and allows them to have a more active and adventurous childhood,” she says.

Almubarak Asra is supervised by Todd Alexander. Her fellowship has been funded by the Stollery Children’s Hospital Foundation through the Women and Children’s Health Research Institute.