TRPM3 variants underlie neurodevelopmental disorders and epileptic encephalopathies

TRPM3 is a temperature- and neurosteroid-sensitive plasma membrane cation channel expressed in a variety of neuronal cells of the peripheral and central nerves system. Recently, the first de novo variants in the TRPM3 gene were identified in individuals with developmental and epileptic encephalopathy (DEE) characterized by developmental delay, intellectual disability, hypotonia and abnormal EEG. The p.(V1027M) variant is the most recurrent TRPM3 mutation as it is detected in 13 out of 15 patients. Own data indicated the V1027M mutation results in a gain-of-function (GoF) mutation of TRPM3. However, the link between TRPM3 activity and the neuronal disease remains poorly understood.
The overall goal of this project is to provide novel insights into the role of TRPM3 in the nervous system. Here, we aim to (1) characterize the gating properties of newly identified disease associated TRPM3 channel variants, (2) map the expression of TRPM3 during brain development, (3) investigate the impact of the GoF TRPM3 mutation (p.V1027M) in the peripheral and central nervous system in vivo using a genetically modified knock-in mice model. Finally, (4) evaluate the potential of TRPM3 antagonists as pharmacological therapy for DEE. The expected outcome of this project is very high as the results will validate TRPM3 as an important locus for DEE. In addition, the obtained results could be of proof-of-concept to show the efficacy of TRPM3 antagonists in countering the GoF TRPM3 channel activity