For Improving diagnostics and Grasping the disease mechanisms of rare Hypomagnesemia in paTients with CNNM2 mutations

• Applicant: Professor Dr. Dominik Müller
• Subject Area: Anatomy and Physiology ; Human Genetics ; Mineralogy, Petrology and Geochemistry
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 441567686

Mutations in CNNM2 membrane proteins were identified to be causative for hypomagnesemia, intellectual disability and seizures. CNNM2 mutations are the most common genetic cause for rare dominant hypomagnesemia. Currently, there are no clinical protocols for the diagnosis and follow-up of patients with CNNM2 mutations. Although it has been described that CNNM2 mutations impair renal magnesium reabsorption, the mechanisms that explain the disease are poorly understood. In this project proposal, we aim to improve diagnostics and the understanding of CNNM2-associated disease by integrated structural, functional and biochemical techniques. Our international network of CNNM2 researchers will address the following key objectives: • Key objective 1: CNNM2 Diagnostics. By systematic phenotyping of CNNM2 patients, a novel diagnostics protocol will be developed. Patient-derived stem cells will be stored in a biobank. • Key objective 2: CNNM2 Structure. The CNNM2 protein structure will be uncovered to understand the impact of patient mutations on protein folding and activity.• Key objective 3: CNNM2 Interactome. By proteomic analysis, we will map the complete CNNM2 interactome and examine the role of interacting proteins on CNNM2 function and cell signalling.• Key objective 4: CNNM2 Function. Using advanced cell, tissue and animal models, the CNNM2 function will be discovered to understand disturbed Mg2+ transport function in patients harboring mutations in CNNM2.Altogether, these findings will improve diagnostics, screening and understanding of rare hypomagnesemia in patients with CNNM2 mutations.

• DFG Programme: Research Grants
• International Connection: Canada, Netherlands, Spain
• Cooperation Partners: Professor Dr. Luis Aldámiz- Echevarría; Dr. Jeroen H.F. de Baaij; Professor Dr. Joost G. J. Hoenderop; Professor Dr. Luis Alfonso Martinez-Cruz; Dr. Michel L. Tremblay