Treatment of proton transport-related congenital disorders of glycosylation by manganese supplementation – TreatProCDG

Glycosylation is a protein and lipid posttranslational modification influencing many biological and physiological processes. Thousands of proteins are ‘glyco-proteins’. As a result, genetic defects in glycosylation pathways lead to mostly severe diseases, called ‘Congenital Disorders of Glycosylation’ (CDG). With more than 160 different types, CDG has become an important group of metabolic diseases. While pathomechanisms of many CDG are at least partially understood treatment options remain elusive despite years of effort. Our two groups in Lille and Göttingen have successfully identified and characterized novel mechanisms of glycosylation regulation evidenced by the characterization of CDG patients with defects in specific metal ion transporters, such as the Mn2+ transporter TMEM165, and Golgi proton V-ATPase subunits, such as V0a2. The number of CDG patients with Golgi proton transport impairment due to defects in one of seven genes is steadily increasing worldwide to reach >150 patients to date without any treatment being available. One of our keystone results is the recent implementation of manganese therapy for a TMEM165-CDG patient in whom a complete normalization of the glycosylation was observed. Preliminary results highlight that the function of TMEM165 could be dependent on the Golgi pH gradient. The rationale of our project is that one part, if not all, of the glycosylation defects in the Golgi proton transport-deficient CDG patients could arise from a lack of manganese within the Golgi rather than direct effects of Golgi pH disturbance on glycosylation enzymes. The overarching goal of this project is then to overcome the lack of treatments for CDG patients with impaired Golgi pH by implementing manganese therapy in these patients. Within this project, we plan to systematically study the impact of manganese supplementation on glycosylation and related cellular dysfunctions and phenotypes. In a stepwise fashion state-of-the-art approaches will be applied to cellular models for different Golgi proton transport defects. Parallel investigations in a mouse model for ATP6V0A2-CDG will give insights into the optimal time window for manganese supplementation and the molecular impact on single cell and tissue levels. Depending on the response to manganese in these cellular models, we will initiate a treatment by manganese supplementation in probands with suitable genetic defects. A cohort of 30 potential probands has already been identified in France and Germany.