Vetro, A., Pelorosso, C., Balestrini, S., Masi, A., Hambleton, S., Argilli, E., Conti, V., Giubbolini, S., Barrick, R., Bergant, G., Writzl, K., Bijlsma, E.K., Brunet, T., Cacheiro, P., Mei, D., Devlin, A., Hoffer, M.J.V., Machol, K., Mannaioni, G., Sakamoto, M., Menezes, M.P., Courtin, T., Sherr, E., Parra, R., Richardson, R., Roscioli, T., Scala, M., von Stülpnagel, C., Smedley, D., TMEM63B collaborators, , Genomics England Research Consortium, , Torella, A., Tohyama, J., Koichihara, R., Hamada, K., Ogata, K., Suzuki, T., Sugie, A., van der Smagt, J.J., van Gassen, K., Valence, S., Vittery, E., Malone, S., Kato, M., Matsumoto, N., Ratto, G.M., Guerrini, R. (2023). Stretch-activated ion channel TMEM63B associates with developmental and epileptic encephalopathies and progressive neurodegeneration.  Am. J. Hum. Genet. 110(8): 1356--1376.

FBrf0257232

Research paper

By converting physical forces into electrical signals or triggering intracellular cascades, stretch-activated ion channels allow the cell to respond to osmotic and mechanical stress. Knowledge of the pathophysiological mechanisms underlying associations of stretch-activated ion channels with human disease is limited. Here, we describe 17 unrelated individuals 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 heterozygous variants of TMEM63B, encoding for a highly conserved stretch-activated ion channel. The variants occurred de novo in 16/17 individuals for whom parental DNA was available and either missense, including the recurrent p.Val44Met in 7/17 individuals, or in-frame, all affecting conserved residues located in transmembrane regions of the protein. In 12 individuals, hematological abnormalities co-occurred, such as macrocytosis and hemolysis, requiring blood transfusions in some. We modeled six variants (p.Val44Met, p.Arg433His, p.Thr481Asn, p.Gly580Ser, p.Arg660Thr, and p.Phe697Leu), each affecting a distinct transmembrane domain of the channel, in transfected Neuro2a cells and demonstrated inward leak cation currents across the mutated channel even in isotonic conditions, while the response to hypo-osmotic challenge was impaired, as were the Ca[2+] transients generated under hypo-osmotic stimulation. Ectopic expression of the p.Val44Met and p.Gly580Cys variants in Drosophila resulted in early death. TMEM63B-associated DEE represents a recognizable clinicopathological entity in which altered cation conductivity results in a severe neurological phenotype with progressive brain damage and early-onset epilepsy associated with hematological abnormalities in most individuals.

PMC10432263 (PMC) (EuropePMC)