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

• DOI: 10.1016/j.ajhg.2023.06.008
• Publication Date: 2023-07-07T14:28:25Z
• Authors: Annalisa Vetro; Cristiana Pelorosso; Simona Balestrini; Alessio Masi; Sophie Hambleton; Emanuela Argilli; Valerio Conti; Simone Giubbolini; Rebekah Barrick; Gaber Bergant; Karin Writzl; Emilia K. Bijlsma; Theresa Brunet; Pilar Cacheiro; Davide Mei; Anita Devlin; Mariëtte J.V. Hoffer; Keren Machol; Guido Mannaioni; Masamune Sakamoto; Manoj P. Menezes; Thomas Courtin; Elliott Sherr; Riccardo Parra; Ruth Richardson; Tony Roscioli; Marcello Scala; Celina von Stülpn...; Damian Smedley; Francesca Pochiero; Francesco Mari; Venkateswaran Ramesh; Valeria Capra; Margherita Mancardi; Boris Keren; Cyiril Mignot; Matteo Lulli; Kendall Parks; Helen Griffin; Melanie Brugger; Vincenzo Nigro; Yuko Hirata; Reiko Koichihara; Borut Peterlin; Yuko Hirata; Ryuto Maki; Yohei Nitta; John C. Ambrose; Prabhu Arumugam; Roel Bevers; Marta Bleda; Freya Boardman-Pr...; Christopher R. Bo...; Helen Brittain; Matthew A. Brown; Mark J. Caulfield; Georgia C. Chan; Adam Giess; John N. Griffin; Angela Hamblin; Shirley Henderson; Tim J.P. Hubbard; Rob Jackson; Louise J. Jones; Dalia Kasperaviciute; Melis Kayikci; Athanasios Kousat...; Lea Lahnstein; Anna Lakey; Sarah E.A. Leigh; Ivonne U.S. Leong; Javier F. Lopez; Fiona Maleady-Crowe; Meriel McEntagart; Federico Minneci; Jonathan Mitchell; Loukas Moutsianas; Michael Mueller; Nirupa Murugaesu; Anna C. Need; Peter O’Donovan; Chris A. Odhams; Christine Patch; Daniel Perez-Gil; Marina B. Pereira; John Pullinger; Tahrima Rahim; Augusto Rendon; Tim Rogers; Kevin Savage; Kushmita Sawant; Richard H. Scott; Afshan Siddiq; Alexander Sieghart; Samuel C. Smith; Alona Sosinsky; Alexander Stuckey; Mélanie Tanguy; Ana Lisa Taylor T...; Ellen R.A. Thomas; Simon R. Thompson; Arianna Tucci; Matthew J. Welland; Eleanor Williams; Katarzyna Witkowska; Suzanne M. Wood; Magdalena Zarowiecki; Annalaura Torella; Jun Tohyama; Reiko Koichihara; Keisuke Hamada; Kazuhiro Ogata; Takashi Suzuki; Atsushi Sugie; Jasper J. van der...; Koen van Gassen; Stephanie Valence; Emma Vittery; Stephen Malone; Mitsuhiro Kato; Naomichi Matsumoto; Gian Michele Ratto; Renzo Guerrini
• Keywords: Brain Diseases; 572; abnormal myelination; epilepsy; epileptic encephalopathy; hemolytic anemia; infantile spasms; ion channels; leak cation currents; osmotic stress; white matter abnormality; abnormal myelination; ion channels; Brain; abnormal myelination; epilepsy; epileptic encephalopathy; hemolytic anemia; infantile spasms; ion channels; leak cation currents; osmotic stress; white matter abnormality.; abnormal myelination, epilepsy, epileptic encephalopathy, hemolytic anemia, infantile spasms, ion channels, leak cation currents, osmotic stress, white matter abnormality; Article; Ion Channels; 3. Good health; epileptic encephalopathy; Phenotype; Intellectual Disability; epilepsy; white matter abnormality; Humans; leak cation currents; osmotic stress; hemolytic anemia; infantile spasms

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.