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

Vetro, Annalisa; Pelorosso, Cristiana; Balestrini, Simona; Masi, Alessio; Hambleton, Sophie; Argilli, Emanuela; Conti, Valerio; Giubbolini, Simone; Barrick, Rebekah; Bergant, Gaber; Writzl, Karin; Bijlsma, Emilia K.; Brunet, Theresa; Cacheiro, Pilar; Mei, Davide; Devlin, Anita; Hoffer, Mariëtte J.V.; Machol, Keren; Mannaioni, Guido; Sakamoto, Masamune; Menezes, Manoj P.; Courtin, Thomas; Sherr, Elliott H.; Parra, Riccardo; Richardson, Ruth; Roscioli, Tony; Scala, Marcello; Stülpnagel, Celina von; Smedley, Damian; Torella, Annalaura; Tohyama, Jun; Hamada, Keisuke; Ogata, Kazuhiro; Suzuki, Takashi; Sugie, Atsushi; Smagt, Jasper J. van der; Gassen, Koen van; Valence, Stéphanie; Vittery, Emma; Malone, Stephen M.; Kato, Mitsuhiro; Matsumoto, Naomichi; Ratto, Gian Michele; Guerrini, Renzo; Pochiero, Francesca; Mari, Francesco; Ramesh, Venkateswaran; Capra, Valeria; Mancardi, Margherita; Keren, Boris; Mignot, Cyril; Lulli, Matteo; Parks, Kendall C.; Griffin, Helen; Brugger, Melanie; Nigro, Vincenzo; Koichihara, Reiko; Peterlin, Borut; Hirata, Yuko; Maki, Ryuto; Nitta, Yohei; Ambrose, J. C.; Arumugam, Prabhu; Bevers, R.; Bleda, Marta; Boardman-Pretty, F.; Boustred, C. R.; Brittain, Helen; Brown, Matthew A.; Caulfield, Mark J.; Chan, G. C.; Giess, Adam; Griffin, John N.; Hamblin, Angela; Henderson, Shirley; Hubbard, Tim; Jackson, R.; Jones, Louise; Kasperavičiūtė, Dalia; Kayikci, Melis; Kousathanas, Athanasios; Lahnstein, L.; Lakey, Anna; Leigh, Sarah; Leong, I. U. S.; López, Javier Ferreiros; Maleady‐Crowe, F.; McEntagart, Meriel; Minneci, Federico; Mitchell, J. D.; Moutsianas, Loukas; Mueller, Michael; Murugaesu, Nirupa; Need, Anna C.; O’Donovan, Peter; Odhams, C. A.; Patch, Christine; Perez-Gil, D.; Pereira, Marina B.; Pullinger, J.; Rahim, T.; Rendon, Augusto; Rogers, T.; Savage, K.; Sawant, K.; Scott, Richard; Siddiq, Afshan; Sieghart, A.; Smith, Samuel C.; Sosinsky, Alona; Stuckey, Alexander; Tanguy, M.; Tavares, Ana Lisa Taylor; Thomas, E. R. A.; Thompson, S. R.; Tucci, Arianna; Welland, M. J.; Williams, Eleanor; Witkowska, K.; Wood, S. M.; Zarowiecki, Magdalena

doi:10.1016/j.ajhg.2023.06.008

Cited by 13 publications

(2 citation statements)

References 47 publications

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“…Subsequent work showed that the TMEM63 protein family members TMEM63A, TMEM63B, and TMEM63C function as monomers; TMEM63A and TMEM63B are activated by patch-clamp–mediated negative membrane pressure; and TMEM63B is permeable to numerous cations including Na + , K + , and Ca 2+ ( 11 , 12 ). Recent studies identify a role for TMEM63A and TMEM63B in neurological development and function ( 11 , 13 ), but the expression and importance of TMEM63 in the lung has not been previously explored.…”

Section: Tmem63: Proposed Link Between Breathing and Surfactant Secre...mentioning

confidence: 99%

A role for TMEM63 in the lung

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2024

Journal of Clinical Investigation

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Surfactants are essential for breathing. Although major progress has been made in the past half century toward an understanding of surfactant secretion mechanisms, the identity of the mechanosensor that couples breathing to surfactant secretion has remained elusive. In this issue of the JCI , Chen, Li, and colleagues provide evidence that the mechanosensor is the transmembrane 63 (TMEM63) ion channel. These findings open new avenues for future research into lung mechanobiology.

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Section: Tmem63: Proposed Link Between Breathing and Surfactant Secre...mentioning

confidence: 99%

A role for TMEM63 in the lung

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2024

Journal of Clinical Investigation

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“…One successful strategy identified a set of genes that are essential for mouse organism development but non-essential for cell proliferation and that are highly constrained according to several metrics. Further comparison of embryo and early adult mouse phenotypes and clinical features observed in patients with variants in genes lacking a molecular diagnosis led to the prioritisation of a subset of previously unreported ‘developmental lethal’ genes, with three of them having been functionally validated as the causative gene for the disorder ( Vetro et al, 2023 ; Cousin et al, 2021 ; Rodger et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Computational identification of disease models through cross-species phenotype comparison

Cacheiro,

Pava,

Parkinson

et al. 2024

Disease Models &Amp; Mechanisms

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The use of standardised phenotyping screens to identify abnormal phenotypes in mouse knockouts, together with the use of ontologies to describe such phenotypic features, allows the implementation of an automated and unbiased pipeline to identify new models of disease by performing phenotype comparisons across species. Using data from the International Mouse Phenotyping Consortium (IMPC), approximately half of mouse mutants are able to mimic, at least partially, the human ortholog disease phenotypes as computed by the PhenoDigm algorithm. We found the number of phenotypic abnormalities in the mouse and the corresponding Mendelian disorder, the pleiotropy and severity of the disease, and the viability and zygosity status of the mouse knockout to be associated with the ability of mouse models to recapitulate the human disorder. An analysis of the IMPC impact on disease gene discovery through a publication-tracking system revealed that the resource has been implicated in at least 109 validated rare disease–gene associations over the last decade.

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A monomeric structure of human TMEM63A protein

Wu,

Shang,

Lü

et al. 2024

Proteins

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OSCA/TMEM63 is a newly identified family of mechanically activated (MA) ion channels in plants and animals, respectively, which convert physical forces into electrical signals or trigger intracellular cascades and are essential for eukaryotic physiology. OSCAs and related TMEM16s and transmembrane channel‐like (TMC) proteins form homodimers with two pores. However, the molecular architecture of the mammalian TMEM63 proteins remains unclear. Here we elucidate the structure of human TMEM63A in the presence of calcium by single particle cryo‐EM, revealing a distinct monomeric architecture containing eleven transmembrane helices. It has structural similarity to the single subunit of the Arabidopsis thaliana OSCA proteins. We locate the ion permeation pathway within the monomeric configuration and observe a nonprotein density resembling lipid. These results lay a foundation for understanding the structural organization of OSCA/TMEM63A family proteins.

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

Cited by 13 publications

References 47 publications

A role for TMEM63 in the lung

A role for TMEM63 in the lung

Computational identification of disease models through cross-species phenotype comparison

A monomeric structure of human TMEM63A protein

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