Stretch-activated ion channel TMEM63B associates with developmental and epileptic encephalopathies and progressive neurodegeneration

Abstract

By converting physical forces into electrical signals or triggering intracellular cascades, stretch-activated ion channels (SACs) allow the cell to respond to osmotic and mechanical stress. Knowledge of the pathophysiological mechanisms underlying associations of SACs with human disease is limited. Here we describe 16 unrelated patients, with severe early onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment, associated with progressive neurodegenerative brain changes, carrying ten distinct de novo variants of TMEM63B, encoding for a highly conserved SAC. Variants were missense, including the recurrent V44M in 7/16 patients, or in-frame, and affected conserved residues located in transmembrane regions of the protein. In 12 patients, haematological abnormalities co-occurred, such as macrocytosis and haemolysis, requiring blood transfusions in some. We modelled V44M, R443H, and T481N in transfected Neuro2a cells and demonstrated leak inward cation currents across the mutated channel even in isotonic conditions, while the response to hypo-osmotic challenge was impaired, as were the Ca2+ transients generated under hypo-osmotic stimulation. Ectopic expression of the V44M and G580C variants in Drosophila resulted in early death. TMEM63B-associated DEE represents a novel clinicopathological entity in which altered cation conductivity results in a severe neurological phenotype with progressive brain damage and early onset epilepsy, associated with haematological abnormalities in most patients.