Project Details
Projekt
Identification of genetic and molecular causes of hypophosphatasia
Applicants
Professor Dr. Florian Barvencik; Dr. Timur Yorgan
Subject Area
Orthopaedics, Traumatology, Reconstructive Surgery
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 517063424
In the context of the clinical research unit ProBone, this project (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. The first work package of P5 is focused on a thorough musculoskeletal diagnostics of affected patients in order to provide individualized therapeutic approaches for these patients. This effort will be greatly supported by analyzing the effect of all identified ALPL variants on enzymatic activity by utilizing an established functional assay. Here we will also evaluate the effect of potentially activity modulating cofactors, such as magnesium or zinc. Furthermore, a molecular analysis of induced pluripotent stem cells from selected patients will provide novel insights into the pathomechanisms of HPP. The second work package will focus on deep phenotyping of a novel mouse model for adult-onset HPP. Here we introduced the E191K variant of TNSALP, representing the most common variant identified in our patient cohort so far. Moreover, since the residual activity of the mutant enzyme was found to be increased more than five-fold by elevated magnesium concentrations, the respective mouse model will give us the opportunity to test an in vivo translation of this activity-augmenting influence. Furthermore, we will explore the effectiveness of other therapeutic approaches, especially in the context of impaired fracture healing. The third work package will focus on the identification and confirmation of genetic variants causing “non-classical” HPP. In fact, since 20 % of the previously analyzed patients with clinical symptoms of HPP did not carry a pathogenic variant of ALPL, these patients will be subjected to thorough genetic analyses. Should we thereby identify candidate disease genes for “non-classical” HPP, functional assays would be set up in a second step. One example for this approach is a case of HPP, which is potentially caused by a pathogenic variant of SMS, encoding spermine synthase. Since initial findings obtained by skeletal phenotyping of a corresponding mouse model essentially confirmed this hypothesis, we will now investigate the effect of polyamines on bone metabolism and TNSALP activity. 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.
DFG Programme
Clinical Research Units
