New gene identified as a cause of a form of brittle bone disease

New Canadian-led research has identified a cause of a form of osteogenesis imperfecta, or brittle bone disease, a group of genetic disorders associated with frequent bone fractures. In studying two unrelated patients with a form of the condition associated with muscle weakness, researchers identified changes in a gene not previously linked with human disease. The gene encodes the protein Secreted Protein Acidic and Rich in Cysteine (SPARC), which enables the collagen in bone to calcify.

The study, published in the May 28 online edition of the American Journal of Human Genetics , is led by The Hospital for Sick Children (SickKids) and the Shriners Hospitals for Children in Montreal and Portland, and is a collaboration with the Ludwig Boltzmann Institute of Osteology in Austria and the Care for Rare Canada Consortium.

Up to 90 per cent of osteogenesis imperfecta cases are due to changes in a protein called collagen type 1. However, the remaining 10 per cent of patients do not have mutations in any of the genes that are known to be associated with the condition. These patients have variations in other proteins responsible for maturing the collagen and making it optimal for bone strength. 

Using whole-exome sequencing, the research team set out to identify the disease-causing genetic defect in two girls with a clinical diagnosis of osteogenesis imperfecta type IV, with symptoms including severe bone fragility and muscle weakness. None of the variants found in these patients occurred in genes previously shown to be associated with bone fragility. In both cases,

the research team identified two variants in SPARC.

“The discovery of the role of SPARC in bone and muscle metabolism opens the door to a better understanding of bone fragility and muscle weakness,” says Dr. Roberto Mendoza-Londono, lead author of the study, and Staff Physician in Clinical and Metabolic Genetics and Project Investigator at SickKids. “This knowledge will help point us toward more tailored treatments for children with this specific type of osteogenesis imperfecta in the future.”

Osteogenesis imperfecta is one of the most common causes of bone fragility in children, with a prevalence of seven cases per 100,000 people in Canada.

The research was supported by Genome Canada, the Canadian Institutes of Health Research, the Ontario Genomics Institute, the Ontario Research Fund, Genome Quebec, Children's Hospital of Eastern Ontario Foundation and SickKids Foundation.