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 18 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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Membrane structure‐responsive lipid scramblase activity of the TMEM63/OSCA family

Miyata,

Nishimura,

Nagata

et al. 2024

FEBS Letters

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Phospholipids are asymmetrically distributed in the plasma membrane (PM), and scramblases disrupt this asymmetry by shuffling phospholipids. We recently identified mouse Tmem63b as a membrane structure‐responsive scramblase. Tmem63b belongs to the TMEM63/OSCA family of ion channels; however, the conservation of the scramblase activity within this family remains unclear. We expressed human TMEM63 paralogs, TMEM63B orthologs, and plant OSCA1.1 in Tmem63b‐deficient mouse pro‐B cells and found that vertebrate TMEM63B orthologs exhibit scramblase activity at the PM. Previously, ten pathogenic human TMEM63B variants were identified, some of which exhibited constitutive scramblase activity. Upon expressing all variants, we found that nine variants displayed constitutive scramblase activity. These results suggest that membrane structure‐responsive scramblase activity at the PM is conserved among vertebrate TMEM63B orthologs.

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

Cited by 18 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

Membrane structure‐responsive lipid scramblase activity of the TMEM63/OSCA family

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