In the context of the clinical research unit ProBone, Project 5 (P5) will be focusing on the identification of genetic and molecular causes of hypophosphatasia (HPP). HPP is a relatively rare congenital metabolic disorder with severe musculoskeletal symptoms including osteomalacia, low bone mass and impaired fracture healing. To date, variants of only one gene, ALPL, have been shown to cause HPP. ALPL encodes tissue non-specific alkaline phosphatase (TNSALP), an enzyme catalyzing the hydrolysis of monophosphate esters such as pyrophosphate. Treatment of patients with HPP remains challenging as an effective enzyme replacement therapy is only available for patients with documented childhood-onset HPP. This project is focused on a thorough musculoskeletal diagnostics of affected patients, molecular analysis of the involved mechanisms, and deep phenotyping of a novel mouse model for adult-onset HPP. This model will be used to explore the effectiveness of other therapeutic approaches, especially in the context of impaired fracture healing. Furthermore, this project will attempt the identification and confirmation of genetic variants causing “nonclassical” HPP, caused by variants in genes other than ALPL. Overall, P5, in close collaboration with all the other ProBone projects, will provide the unique opportunity to gain novel insights into genotype/phenotype correlations and underlying pathomechanisms of different subtypes of HPP.

Department of Osteology and Biomechanics