Primary failure of tooth eruption due to heterozygous mutations in the PTH1 receptor gene: Generation and characterization of cell models with clinically relevant mutations and development of therapeutic strategies.
Final Report Abstract
Primary failure of tooth eruption is a rare but serious dental condition for the patients affected. Teeth break through incompletely or in the wrong position into the oral cavity, so that the teeth of the upper and lower jaw do not form the functionally required tooth contact and the chewing function is thus largely disturbed. To date, there is no causal treatment option and therapeutic attempts to improve chewing function by means of conservative or prothetic dental abutments are usually only compromise solutions. The orderly eruption of teeth into the oral cavity and the positioning of the teeth in the correct place is dependent on coordinated remodeling processes in the area of the jaw bone and the connective tissue structures. A large number of signaling molecules and cell systems involved interact with each other, for example bone-building osteoblasts, bone-degrading osteoclasts and cells of the periodontium. Disturbances in these interactions lead to pathologically altered tooth positions with all their clinical consequences for the patient. In addition to mechanical obstacles in the tooth eruption pathway, a genetic cause of this so-called primary failure of tooth eruption disorder was also suspected for decades due to a familial accumulation, but it was not until the beginning of the 21st century that several research groups were able to link mutations of the parathyroid hormone receptor to this disease. By now, well over 50 different heterozygous mutations in this receptor, which is crucial for bone metabolism and tooth eruption, are known and many, but not all, are associated with the clinical picture of a primary tooth eruption disorder. In this research project, for the first time cell culture models have been generated and established that allow these different mutations of the parathyroid hormone receptor to be expressed and characterized in the respective cells. This was carried out for several mutants with regard to regulation of cell motility, regulation of intracellular messenger molecules (including cyclic adenosine monophosphate or calcium) and the regulation of intracellular signaling molecules (vasodilator-stimulated phosphoprotein (VASP) and components of the cytoskeleton). The availability of such cell models now allows further known parathyroid hormone receptor mutants to be characterized with regard to their functional effects. From this, possible therapeutic options can be derived and subsequently tested on these cell systems with the long-term goal of being able to offer patients with this debilitating disease a causal therapy.
Publications
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Die Rolle des Parathormonrezeptors Typ 1 bei der primären Zahndurchbruchsstörung. Osteologie, 31(02), 106-110.
Wiesler, Martina; Stellzig-Eisenhauer, Angelika & Eigenthaler, Martin
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MuSkITYR Symposium 2022, Frankfurt, Establishment of transgenic cell lines with heterozygous mutations in the PTH1 receptor via CRISPR/Cas9
Marnet K., Wiesler M., Eigenthaler M. & Herrmann M.
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Präklinische Zell- und Tiermodelle zur Untersuchung der Auswirkungen des Parathormons auf den Zahnhalteapparat. Osteologie, 31(02), 100-105.
Marnet, Katharina; Schiffmaier, Jana & Herrmann, Marietta
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DGKFO 2023, Stuttgart, Einbringen der heterozygoten c.G1016A PTH1R Variante in parodontale Ligamentzellen zur molekularen Erforschung der primären Zahneruptionsstörung
Marnet K., Wiesler M., Borst A., Liedtke D., Eigenthaler M. & Herrmann M.
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ECTS 2024, Marseille, Frankreich, Characterization of the clinical proven c.1050-3C>G PTH1R variant in periodontal ligament cells via live cell imaging to study molecular effects of primary failure of eruption
Marnet K., Subramanian H., Wiesler M., Borst A., Liedtke D., Docheva D., Nikolaev V., Eigenthaler M. & Herrmann M.
