Skeletal Genomics

National Human Genome Research Institute

Investigators

Linked publications & trials

Abstract

Our group has continued to focus on the clinical characterization of patients with rare skeletal dysplasias. In the past year, we characterized the degree of morbidity from enthesis calcification and related musculoskeletal complications in adult patients with ENPP1 deficiency, using various Patient-Related Outcomes (PRO) tools such as the Brief Pain Inventory (BPI) and PROMIS scores. In addition, this same work showed the potential effect of enzyme replacement therapy in preventing enthesis calcification in a mouse model of the disease (reference 1). We also published the results of a multinational natural history study with more than 200 patients with ENPP1 or ABCC6 deficiency (reference 2), providing valuable data regarding the prognosis of the disease with standard of care, as well as the effect of bisphosphonates on disease outcome, a longstanding question in the field. We recently characterized the hearing phenotype of patients with ENPP1 deficiency, manifested by conductive hearing loss due to ossicular chain dysfunction, and provided evidence that this dysfunction might be related to abnormal perilacunar remodeling of middle ear ossicles as shown in a mouse model of the disease (manuscript accepted). We have continued to characterize our knock-in animal model osteoglophonic dysplasia, a rare disorder characterized by short stature, bone lesions, and increased secretion of a hormone, FGF23, an important regulator of phosphorus levels. We are studying the cell biology in bone cells to gain insight into the currently unknown mechanism of FGF23 increase via various genomic technologies, such as transcriptomics and phosphoproteomics. Our animal model, the first for this rare disease, might be amenable to targeted therapy via a small molecule, an avenue that we will pursue in future work.