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

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.; Stülpnagel, C. von; Smedley, D.; Torella, A.; Tohyama, J.; Koichihara, R.; Hamada, K.; Ogata, K.; Suzuki, T.; Sugie, A.; Smagt, J.J. van der; Gassen, K. van; Valence, S.; Vittery, E.; Malone, S.; Kato, M.; Matsumoto, N.; Ratto, G.M.; Guerrini, R.; Genomics England Res Consortium

doi:doi:10.1016/j.ajhg.2023.06.008

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 Show more 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 Ca²⁺ 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.
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Stretch-activated ion channel TMEM63B associates with developmental and epileptic encephalopathies and progressive neurodegeneration