The role of TGDS in skeletal development and the pathophysiology of Catel- Manzke syndrome

• Applicant: Dr. Nadja Ehmke
• Subject Area: Human Genetics
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 448305421

We have identified mutations in the gene TGDS, whose function is largely unknown, as the cause of skeletal dysplasia Catel-Manzke syndrome. Orthologues of the TGDS protein are already found in bacteria and it is evolutionarily conserved, but the bacterial metabolic pathway does not exist in mammals. First results suggest a role of TGDS in proteoglycan metabolism. In the project "The role of TGDS in skeletal development and the pathophysiology of Catel-Manzke syndrome" the function of TGDS will be investigated in vitro and in a mouse model. Tgds-deficient mice show skeletal changes that resemble Catel-Manzke syndrome. The knockout of Tgds is lethal, therefore compound heterozygous animals carrying a loss-of-function allele and a missense allele will be used for the project. The missense allele corresponds to the most common human mutation. This mouse model has already been established and will be analyzed within the project with respect to skeletal phenotype, signaling pathways relevant for skeletal development and proteoglycan metabolism. In addition to the above mentioned aspects, the localization of TGDS and the TGDS interactome will be determined in vitro. For the in vitro analyses, different cell models will be used, including murine and human chondrocytes edited by CRISPR/Cas. In addition, genome sequencing will be used to identify the cause of Catel-Manzke-like phenotypes, which could be based on mutations in proteins in related metabolic pathways. The results will improve our understanding of skeletal development and proteoglycan metabolism

• DFG Programme: Research Grants