Stretch-activated ion channel TMEM63B associates with developmental and epileptic encephalopathies and progressive neurodegeneration.
dc.contributor.author | Vetro, A | |
dc.contributor.author | Pelorosso, C | |
dc.contributor.author | Balestrini, S | |
dc.contributor.author | Masi, A | |
dc.contributor.author | Hambleton, S | |
dc.contributor.author | Argilli, E | |
dc.contributor.author | Conti, V | |
dc.contributor.author | Giubbolini, S | |
dc.contributor.author | Barrick, R | |
dc.contributor.author | Bergant, G | |
dc.contributor.author | Writzl, K | |
dc.contributor.author | Bijlsma, EK | |
dc.contributor.author | Brunet, T | |
dc.contributor.author | Cacheiro, P | |
dc.contributor.author | Mei, D | |
dc.contributor.author | Devlin, A | |
dc.contributor.author | Hoffer, MJV | |
dc.contributor.author | Machol, K | |
dc.contributor.author | Mannaioni, G | |
dc.contributor.author | Sakamoto, M | |
dc.contributor.author | Menezes, MP | |
dc.contributor.author | Courtin, T | |
dc.contributor.author | Sherr, E | |
dc.contributor.author | Parra, R | |
dc.contributor.author | Richardson, R | |
dc.contributor.author | Roscioli, T | |
dc.contributor.author | Scala, M | |
dc.contributor.author | von Stülpnagel, C | |
dc.contributor.author | Smedley, D | |
dc.contributor.author | TMEM63B collaborators | |
dc.contributor.author | Genomics England Research Consortium | |
dc.contributor.author | Torella, A | |
dc.contributor.author | Tohyama, J | |
dc.contributor.author | Koichihara, R | |
dc.contributor.author | Hamada, K | |
dc.contributor.author | Ogata, K | |
dc.contributor.author | Suzuki, T | |
dc.contributor.author | Sugie, A | |
dc.contributor.author | van der Smagt, JJ | |
dc.contributor.author | van Gassen, K | |
dc.contributor.author | Valence, S | |
dc.contributor.author | Vittery, E | |
dc.contributor.author | Malone, S | |
dc.contributor.author | Kato, M | |
dc.contributor.author | Matsumoto, N | |
dc.contributor.author | Ratto, GM | |
dc.contributor.author | Guerrini, R | |
dc.date.accessioned | 2024-07-15T09:32:55Z | |
dc.date.available | 2023-06-13 | |
dc.date.available | 2024-07-15T09:32:55Z | |
dc.date.issued | 2023-08-03 | |
dc.identifier.citation | TY - JOUR T1 - Stretch-activated ion channel TMEM63B associates with developmental and epileptic encephalopathies and progressive neurodegeneration AU - Vetro, Annalisa AU - Pelorosso, Cristiana AU - Balestrini, Simona AU - Masi, Alessio AU - Hambleton, Sophie AU - Argilli, Emanuela AU - Conti, Valerio AU - Giubbolini, Simone AU - Barrick, Rebekah AU - Bergant, Gaber AU - Writzl, Karin AU - Bijlsma, Emilia K. AU - Brunet, Theresa AU - Cacheiro, Pilar AU - Mei, Davide AU - Devlin, Anita AU - Hoffer, Mariëtte J.V. AU - Machol, Keren AU - Mannaioni, Guido AU - Sakamoto, Masamune AU - Menezes, Manoj P. AU - Courtin, Thomas AU - Sherr, Elliott AU - Parra, Riccardo AU - Richardson, Ruth AU - Roscioli, Tony AU - Scala, Marcello AU - von Stülpnagel, Celina AU - Smedley, Damian AU - Pochiero, Francesca AU - Mari, Francesco AU - Ramesh, Venkateswaran AU - Capra, Valeria AU - Mancardi, Margherita AU - Keren, Boris AU - Mignot, Cyiril AU - Lulli, Matteo AU - Parks, Kendall AU - Griffin, Helen AU - Brugger, Melanie AU - Nigro, Vincenzo AU - Hirata, Yuko AU - Koichihara, Reiko AU - Peterlin, Borut AU - Hirata, Yuko AU - Maki, Ryuto AU - Nitta, Yohei AU - Ambrose, John C. AU - Arumugam, Prabhu AU - Bevers, Roel AU - Bleda, Marta AU - Boardman-Pretty, Freya AU - Boustred, Christopher R. AU - Brittain, Helen AU - Brown, Matthew A. AU - Caulfield, Mark J. AU - Chan, Georgia C. AU - Giess, Adam AU - Griffin, John N. AU - Hamblin, Angela AU - Henderson, Shirley AU - Hubbard, Tim J.P. AU - Jackson, Rob AU - Jones, Louise J. AU - Kasperaviciute, Dalia AU - Kayikci, Melis AU - Kousathanas, Athanasios AU - Lahnstein, Lea AU - Lakey, Anna AU - Leigh, Sarah E.A. AU - Leong, Ivonne U.S. AU - Lopez, Javier F. AU - Maleady-Crowe, Fiona AU - McEntagart, Meriel AU - Minneci, Federico AU - Mitchell, Jonathan AU - Moutsianas, Loukas AU - Mueller, Michael AU - Murugaesu, Nirupa AU - Need, Anna C. AU - O’Donovan, Peter AU - Odhams, Chris A. AU - Patch, Christine AU - Perez-Gil, Daniel AU - Pereira, Marina B. AU - Pullinger, John AU - Rahim, Tahrima AU - Rendon, Augusto AU - Rogers, Tim AU - Savage, Kevin AU - Sawant, Kushmita AU - Scott, Richard H. AU - Siddiq, Afshan AU - Sieghart, Alexander AU - Smith, Samuel C. AU - Sosinsky, Alona AU - Stuckey, Alexander AU - Tanguy, Mélanie AU - Taylor Tavares, Ana Lisa AU - Thomas, Ellen R.A. AU - Thompson, Simon R. AU - Tucci, Arianna AU - Welland, Matthew J. AU - Williams, Eleanor AU - Witkowska, Katarzyna AU - Wood, Suzanne M. AU - Zarowiecki, Magdalena AU - Torella, Annalaura AU - Tohyama, Jun AU - Koichihara, Reiko AU - Hamada, Keisuke AU - Ogata, Kazuhiro AU - Suzuki, Takashi AU - Sugie, Atsushi AU - van der Smagt, Jasper J. AU - van Gassen, Koen AU - Valence, Stephanie AU - Vittery, Emma AU - Malone, Stephen AU - Kato, Mitsuhiro AU - Matsumoto, Naomichi AU - Ratto, Gian Michele AU - Guerrini, Renzo Y1 - 2023/08/03 PY - 2023 N1 - doi: 10.1016/j.ajhg.2023.06.008 DO - 10.1016/j.ajhg.2023.06.008 T2 - The American Journal of Human Genetics JF - The American Journal of Human Genetics SP - 1356 EP - 1376 VL - 110 IS - 8 PB - Elsevier SN - 0002-9297 M3 - doi: 10.1016/j.ajhg.2023.06.008 UR - https://doi.org/10.1016/j.ajhg.2023.06.008 Y2 - 2024/07/15 ER - | en_US |
dc.identifier.uri | https://qmro.qmul.ac.uk/xmlui/handle/123456789/98118 | |
dc.description.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 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. | en_US |
dc.format.extent | 1356 - 1376 | |
dc.language | eng | |
dc.publisher | Elsevier | en_US |
dc.relation.ispartof | Am J Hum Genet | |
dc.rights | This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). | |
dc.subject | abnormal myelination | en_US |
dc.subject | epilepsy | en_US |
dc.subject | epileptic encephalopathy | en_US |
dc.subject | hemolytic anemia | en_US |
dc.subject | infantile spasms | en_US |
dc.subject | ion channels | en_US |
dc.subject | leak cation currents | en_US |
dc.subject | osmotic stress | en_US |
dc.subject | white matter abnormality | en_US |
dc.subject | Humans | en_US |
dc.subject | Brain Diseases | en_US |
dc.subject | Ion Channels | en_US |
dc.subject | Brain | en_US |
dc.subject | Intellectual Disability | en_US |
dc.subject | Phenotype | en_US |
dc.title | Stretch-activated ion channel TMEM63B associates with developmental and epileptic encephalopathies and progressive neurodegeneration. | en_US |
dc.type | Article | en_US |
dc.rights.holder | © 2023 The Authors. | |
dc.identifier.doi | 10.1016/j.ajhg.2023.06.008 | |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/37421948 | en_US |
pubs.issue | 8 | en_US |
pubs.notes | Not known | en_US |
pubs.publication-status | Published | en_US |
pubs.volume | 110 | en_US |
dcterms.dateAccepted | 2023-06-13 | |
rioxxterms.funder | Default funder | en_US |
rioxxterms.identifier.project | Default project | en_US |
rioxxterms.funder.project | b215eee3-195d-4c4f-a85d-169a4331c138 | en_US |