Beating ADKH-RRAGD: The role of the mTORC1 signaling pathway, and therapeutic perspectives

A group of patients displaying magnesium deficiency accompanied by the calcium accumulation in the kidney was identified in 2020. In half of these patients, enlargement of the heart chamber termed dilated cardiomyopathy was diagnosed. Upon genetic screening, various variants in a gene called RRAGD were discovered. This thesis aimed to identify how these variants change cellular functions and explored potential therapies for patients. We found that most of the variants caused the constant activation of an important signaling pathway that regulates cell growth and proliferation, and this may correlate with the disease severity. Furthermore, we developed heart models and confirmed that RRAGD variants are causing cardiac dysfunction in these models. Lastly, we explored potential therapies for patients and found that dapagliflozin can improve magnesium deficiency by 10% in patients. Future research should aim to uncover the molecular cause of this disease to provide targeted therapeutic options for patients.