Stretch-activated ion channel TMEM63B associates with developmental and epileptic encephalopathies and progressive neurodegeneration
Annalisa Vetro, Cristiana Pelorosso, Simona Balestrini, Alessio Masi, Sophie Hambleton, Emanuela Argilli, Valerio Conti, Simone Giubbolini, Rebekah Barrick, Gaber Bergant, Karin Writzl, Emilia K. Bijlsma, Theresa Brunet, Pilar Cacheiro, Davide Mei, Anita Devlin, Mariëtte J.V. Hoffer, Keren Machol, Guido Mannaioni, Masamune Sakamoto, Manoj P. Menezes, Thomas Courtin, Elliott H. Sherr, Riccardo Parra, Ruth Richardson, Tony Roscioli, Marcello Scala, Celina von Stülpnagel, Damian Smedley, Francesca Pochiero, Francesco Mari, Venkateswaran Ramesh, Valeria Capra, Margherita Mancardi, Boris Keren, C. Mignot, Matteo Lulli, Kendall C. Parks, Helen Griffin, Melanie Brügger, Vincenzo Nigro, Yuko Hirata, Reiko Koichihara, Borut Peterlin, Yuko Hirata, Ryuto Maki, Yohei Nitta, John C. Ambrose, Prabhu Arumugam, R. Bevers, Marta Bleda, Freya Boardman-Pretty, C. R. Boustred, Helen Brittain, Matthew A. Brown, Mark J. Caulfield, G. C. Chan, Adam Giess, John N. Griffin, Angela Hamblin, Shirley Henderson, Tim Hubbard, Robert B. Jackson, Louise J. Jones, Dalia Kasperavičiūtė, Melis Kayikci, Athanasios Kousathanas, L. Lahnstein, Anna Lakey, S. E. A. Leigh, I. U. S. Leong, Javier Ferreiros, F. Maleady-Crowe, Meriel McEntagart, Federico Minneci, Jonathan Mitchell, Loukas Moutsianas, Michael P. Mueller, Nirupa Murugaesu, Anna C. Need, Peter O’Donovan, Chris A. Odhams, Christine Patch, D. Perez-Gil, Marina B. Pereira, J. Pullinger, T. Rahim, Augusto Rendon, Tim Rogers, K. Savage, Kushmita Sawant, Richard H. Scott, Afshan Siddiq, A. Sieghart, Samuel C. Smith, Alona Sosinsky, Alexander Stuckey, M. Tanguy, Ana Lisa Taylor Tavares, Ellen Thomas
Abstract
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.