Skeletal Genomics

National Human Genome Research Institute

Investigators

Linked publications, trials & patents

Abstract

Our group has continued to focus on the clinical characterization of patients with rare skeletal dysplasias. In the past year, we delineated the natural history of surviving patients with ENPP1 deficiency (reference 1), a rare disorder characterized by ectopic calcification and high mortality in early life, and rickets or osteomalacia in later life. We have characterized the skeletal and renal presentations of the disease in patients, and collaborated to describe the effect of enzyme replacement therapy on the skeletal and renal manifestations of the animal model (reference 2). We also called attention to the fact that certain biologic agents should be avoided in this patient population, as they could lead to worsening ectopic calcification, a fact that could have important implications in patient management (reference 3). We have collaborated with extramural investigators to expand knowledge of mouse models of skeletal dysplasias (reference 4), characterize the skeletal phenotype of rare genetic disorders (reference 5), and review the status of clinical management and research related to skeletal dysplasias in Latin America (reference 6). Active efforts include the development of a knock-in animal model of a rare skeletal disorder, osteoglophonic dysplasia, in collaboration with the NHGRI Transgenic Mouse Core. Osteoglophonic dysplasia is characterized by short stature, bone lesions, and increased secretion of a hormone, FGF23, an important regulator of phosphorus levels. This represents the first animal model of this rare disease, and might be amenable to targeted therapy via a small molecule. We plan to better characterize the mouse model and its response to therapy, and study the cell biology in bone marrow stromal cells to gain insight into the currently-unknown mechanism of FGF23 increase.