Details

Autor(en) / Beteiligte

• Vetro, Annalisa
• Pelorosso, Cristiana
• Balestrini, Simona
• Masi, Alessio
• Hambleton, Sophie
• Argilli, Emanuela
• Giubbolini, Simone
• Barrick, Rebekah
• Bergant, Gaber
• Writzl, Karin
• Bijlsma, Emilia K.
• Cacheiro, Pilar
• Mei, Davide
• Devlin, Anita
• Machol, Keren
• Mannaioni, Guido
• Sakamoto, Masamune
• Menezes, Manoj P.
• Courtin, Thomas
• Sherr, Elliott
• Parra, Riccardo
• Richardson, Ruth
• Roscioli, Tony
• Scala, Marcello
• von Stülpnagel, Celina
• Smedley, Damian
• Pochiero, Francesca
• Ramesh, Venkateswaran
• Capra, Valeria
• Mancardi, Margherita
• Keren, Boris
• Mignot, Cyiril
• Lulli, Matteo
• Parks, Kendall
• Griffin, Helen
• Nigro, Vincenzo
• Hirata, Yuko
• Koichihara, Reiko
• Peterlin, Borut
• Maki, Ryuto
• Nitta, Yohei
• Ambrose, John C.
• Arumugam, Prabhu
• Bevers, Roel
• Bleda, Marta
• Boustred, Christopher R.
• Brittain, Helen
• Brown, Matthew A.
• Caulfield, Mark J.
• Chan, Georgia C.
• Giess, Adam
• Griffin, John N.
• Hamblin, Angela
• Henderson, Shirley
• Hubbard, Tim J.P.
• Jackson, Rob
• Jones, Louise J.
• Kasperaviciute, Dalia
• Kayikci, Melis
• Kousathanas, Athanasios
• Lahnstein, Lea
• Lakey, Anna
• Lopez, Javier F.
• Maleady-Crowe, Fiona
• Minneci, Federico
• Mueller, Michael
• Murugaesu, Nirupa
• Need, Anna C.
• O’Donovan, Peter
• Odhams, Chris A.
• Patch, Christine
• Rahim, Tahrima
• Rendon, Augusto
• Sawant, Kushmita
• Siddiq, Afshan
• Sieghart, Alexander
• Smith, Samuel C.
• Stuckey, Alexander
• Tanguy, Mélanie
• Taylor Tavares, Ana Lisa
• Thomas, Ellen R.A.
• Tucci, Arianna
• Welland, Matthew J.
• Williams, Eleanor
• Witkowska, Katarzyna
• Wood, Suzanne M.
• Zarowiecki, Magdalena
• Torella, Annalaura
• Tohyama, Jun
• Hamada, Keisuke
• Ogata, Kazuhiro
• Sugie, Atsushi
• van der Smagt, Jasper J.
• van Gassen, Koen
• Valence, Stephanie
• Vittery, Emma
• Malone, Stephen
• Kato, Mitsuhiro
• Ratto, Gian Michele
• Guerrini, Renzo

Titel

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

Ist Teil von

• American journal of human genetics, 2023-08, Vol.110 (8), p.1356-1376

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] Combining in silico evaluation, in vitro electrophysiology and Ca2+ imaging, and in vivo modeling in Drosophila, Vetro et al. demonstrate that gain-of-function variants of the stretch-activated ion channel TMEM63B cause a severe neurodevelopmental disorder with early-onset epilepsy and progressive brain damage associated with hematological abnormalities in most individuals.