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

Lookup NU author(s): Professor Sophie HambletonORCiD, Dr Ruth Richardson



This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


© 2023 The Author(s)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.

Publication metadata

Author(s): Vetro A, Pelorosso C, Balestrini S, Masi A, Hambleton S, Argilli E, Conti V, Giubbolini S, Barrick R, Bergant G, Writzl K, Bijlsma EK, Brunet T, Cacheiro P, Mei D, Devlin A, Hoffer MJV, Machol K, Mannaioni G, Sakamoto M, Menezes MP, Courtin T, Sherr E, Parra R, Richardson R, Roscioli T, Scala M, von Stulpnagel C, Smedley D, Pochiero F, Mari F, Ramesh V, Capra V, Mancardi M, Keren B, Mignot C, Lulli M, Parks K, Griffin H, Brugger M, Nigro V, Hirata Y, Koichihara R, Peterlin B, Maki R, Nitta Y, Ambrose JC, Arumugam P, Bevers R, Bleda M, Boardman-Pretty F, Boustred CR, Brittain H, Brown MA, Caulfield MJ, Chan GC, Giess A, Griffin JN, Hamblin A, Henderson S, Hubbard TJP, Jackson R, Jones LJ, Kasperaviciute D, Kayikci M, Kousathanas A, Lahnstein L, Lakey A, Leigh SEA, Leong IUS, Lopez JF, Maleady-Crowe F, McEntagart M, Minneci F, Mitchell J, Moutsianas L, Mueller M, Murugaesu N, Need AC, O'Donovan P, Odhams CA, Patch C, Perez-Gil D, Pereira MB, Pullinger J, Rahim T, Rendon A, Rogers T, Savage K, Sawant K, Scott RH, Siddiq A, Sieghart A, Smith SC, Sosinsky A, Stuckey A, Tanguy M, Taylor Tavares AL, Thomas ERA, Thompson SR, Tucci A, Welland MJ, Williams E, Witkowska K, Wood SM, Zarowiecki M, Torella A, Tohyama J, Hamada K, Ogata K, Suzuki T, Sugie A, van der Smagt JJ, van Gassen K, Valence S, Vittery E, Malone S, Kato M, Matsumoto N, Ratto GM, Guerrini R

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2023

Volume: 110

Issue: 8

Pages: 1356-1376

Print publication date: 03/08/2023

Online publication date: 07/07/2023

Acceptance date: 13/06/2023

Date deposited: 18/09/2023

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press


DOI: 10.1016/j.ajhg.2023.06.008

Data Access Statement: The data supporting the findings of this study are available within the article and/or its supplemental information. The exome datasets supporting this study have not been deposited in a public repository due to privacy and ethical/legal issues. TMEM63B genetic variants identified in our study have been submitted to DECIPHER (; accession IDs 512417 and 512438–512452). Any additional raw data are available on request from the corresponding author.

PubMed id: 37421948


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