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1. ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy.

Author

Mattison, Kari, Tossing, Gilles, Mulroe, Fred, Simmons, Callum, Butler, Kameryn, Schreiber, Alison, Alsadah, Adnan, Neilson, Derek, Naess, Karin, Wedell, Anna, Wredenberg, Anna, Sorlin, Arthur, McCann, Emma, Burghel, George, Menendez, Beatriz, Hoganson, George, Botto, Lorenzo, Filloux, Francis, Aledo-Serrano, Ángel, Gil-Nagel, Antonio, Tatton-Brown, Katrina, Verbeek, Nienke, van der Zwaag, Bert, Aleck, Kyrieckos, Fazenbaker, Andrew, Balciuniene, Jorune, Dubbs, Holly, Marsh, Eric, Garber, Kathryn, Ek, Jakob, Duno, Morten, Hoei-Hansen, Christina, Deardorff, Matthew, Raca, Gordana, Quindipan, Catherine, van Hirtum-Das, Michele, Breckpot, Jeroen, Hammer, Trine, Møller, Rikke, Whitney, Andrea, Douglas, Andrew, Kharbanda, Mira, Brunetti-Pierri, Nicola, Morleo, Manuela, Nigro, Vincenzo, May, Halie, Tao, James, Sherr, Elliot, Dobyns, William, Baines, Richard, Warwicker, Jim, Parker, J, Banka, Siddharth, Campeau, Philippe, Escayg, Andrew, and Argilli, Emanuela

Subjects
ATP6V0C, V-ATPase, VMA3, epilepsy genetics, neurodevelopmental disorders, Humans, Vacuolar Proton-Translocating ATPases, Saccharomyces cerevisiae, Epilepsy, Adenosine Triphosphate
Abstract

The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms.

Published
2023

4. Subclinical early posttraumatic seizures detected by continuous EEG monitoring in a consecutive pediatric cohort

Author

Arndt, Daniel H, Lerner, Jason T, Matsumoto, Joyce H, Madikians, Andranik, Yudovin, Sue, Valino, Hannah, McArthur, David L, Wu, Joyce Y, Leung, Michelle, Buxey, Farzad, Szeliga, Conrad, Van Hirtum‐Das, Michele, Sankar, Raman, Brooks‐Kayal, Amy, and Giza, Christopher C

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Childhood Injury, Traumatic Head and Spine Injury, Brain Disorders, Traumatic Brain Injury (TBI), Neurosciences, Neurodegenerative, Physical Injury - Accidents and Adverse Effects, Clinical Research, Pediatric, Epilepsy, Injuries and accidents, Adolescent, Anticonvulsants, Brain Injuries, Child, Child, Preschool, Electroencephalography, Epilepsies, Partial, Female, Glasgow Coma Scale, Humans, Infant, Male, Monitoring, Physiologic, Prospective Studies, Risk Factors, Seizures, Status Epilepticus, Clinical neurophysiology, Children, ICU, Neurology & Neurosurgery, Clinical sciences
Abstract

PurposeTraumatic brain injury (TBI) is an important cause of morbidity and mortality in children, and early posttraumatic seizures (EPTS) are a contributing factor to ongoing acute damage. Continuous video-EEG monitoring (cEEG) was utilized to assess the burden of clinical and electrographic EPTS.MethodsEighty-seven consecutive, unselected (mild - severe), acute TBI patients requiring pediatric intensive care unit (PICU) admission at two academic centers were monitored prospectively with cEEG per established clinical TBI protocols. Clinical and subclinical seizures and status epilepticus (SE, clinical and subclinical) were assessed for their relation to clinical risk factors and short-term outcome measures.Key findingsOf all patients, 42.5% (37/87) had seizures. Younger age (p = 0.002) and injury mechanism (abusive head trauma - AHT, p < 0.001) were significant risk factors. Subclinical seizures occurred in 16.1% (14/87), while 6.9% (6/87) had only subclinical seizures. Risk factors for subclinical seizures included younger age (p < 0.001), AHT (p < 0.001), and intraaxial bleed (p < 0.001). SE occurred in 18.4% (16/87) with risk factors including younger age (p < 0.001), AHT (p < 0.001), and intraaxial bleed (p = 0.002). Subclinical SE was detected in 13.8% (12/87) with significant risk factors including younger age (p < 0.001), AHT (p = 0.001), and intraaxial bleed (p = 0.004). Subclinical seizures were associated with lower discharge King's Outcome Scale for Childhood Head Injury (KOSCHI) score (p = 0.002). SE and subclinical SE were associated with increased hospital length of stay (p = 0.017 and p = 0.041, respectively) and lower hospital discharge KOSCHI (p = 0.007 and p = 0.040, respectively).SignificancecEEG monitoring significantly improves detection of seizures/SE and is the only way to detect subclinical seizures/SE. cEEG may be indicated after pediatric TBI, particularly in younger children, AHT cases, and those with intraaxial blood on computerized tomography (CT).

Published
2013

5. ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy

Author

Mattison, Kari A, Tossing, Gilles, Mulroe, Fred, Simmons, Callum, Butler, Kameryn M, Schreiber, Alison, Alsadah, Adnan, Neilson, Derek E, Naess, Karin, Wedell, Anna, Wredenberg, Anna, Sorlin, Arthur, McCann, Emma, Burghel, George J, Menendez, Beatriz, Hoganson, George E, Botto, Lorenzo D, Filloux, Francis M, Aledo-Serrano, Angel, Gil-Nagel, Antonio, Tatton-Brown, Katrina, Verbeek, Nienke E, van der Zwaag, Bert, Aleck, Kyrieckos A, Fazenbaker, Andrew C, Balciuniene, Jorune, Dubbs, Holly A, Marsh, Eric D, Garber, Kathryn, Ek, Jakob, Duno, Morten, Hoei-Hansen, Christina E, Deardorff, Matthew A, Raca, Gordana, Quindipan, Catherine, Van Hirtum-Das, Michele, Breckpot, Jeroen, Hammer, Trine Bjorg, Moller, Rikke S, Whitney, Andrea, Douglas, Andrew GL, Kharbanda, Mira, Brunetti-Pierri, Nicola, Morleo, Manuela, Nigro, Vincenzo, May, Halie J, Tao, James X, Argilli, Emanuela, Sherr, Elliot H, Dobyns, William B, Baines, Richard A, Warwicker, Jim, Parker, J Alex, Banka, Siddharth, Campeau, Philippe M, and Escayg, Andrew

Subjects
neurodevelopmental disorders, ATP6V0C, VMA3, V-ATPase, Neurology (clinical), epilepsy genetics
Abstract

The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms. ispartof: BRAIN vol:146 issue:4 ispartof: location:England status: Published online

Published
2023

6. ATP6V0C variants impair vacuolar V-ATPase causing a neurodevelopmental disorder often associated with epilepsy

Author

Mattison, Kari A, Tossing, Gilles, Mulroe, Fred, Simmons, Callum, Butler, Kameryn M, Schreiber, Alison, Alsadah, Adnan, Neilson, Derek E, Naess, Karin, Wedell, Anna, Wredenberg, Anna, Sorlin, Arthur, McCann, Emma, Burghel, George J, Menendez, Beatriz, Hoganson, George E, Botto, Lorenzo D, Filloux, Francis M, Aledo-Serrano, Ángel, Gil-Nagel, Antonio, Tatton-Brown, Katrina, Verbeek, Nienke E, van Hirtum-Das, Michele, Breckpot, Jeroen, Hammer, Trine Bjørg, Møller, Rikke S, Whitney, Andrea, Douglas, Andrew G L, Kharbanda, Mira, Brunetti-Pierri, Nicola, Morleo, Manuela, Nigro, Vincenzo, May, Halie J, Tao, James X, Argili, Emanuela, Sherr, Elliot H, Dobyns, William B, Consortium, Genomics England Research, Baines, Richard A, Warwicker, Jim, Parker, J Alex, Banka, Siddharth, Campeau, Philippe M, Escayg, Andrew, Mattison, Kari A, Tossing, Gille, Mulroe, Fred, Simmons, Callum, Butler, Kameryn M, Schreiber, Alison, Alsadah, Adnan, Neilson, Derek E, Naess, Karin, Wedell, Anna, Wredenberg, Anna, Sorlin, Arthur, Mccann, Emma, Burghel, George J, Menendez, Beatriz, Hoganson, George E, Botto, Lorenzo D, Filloux, Francis M, Aledo-Serrano, Ángel, Gil-Nagel, Antonio, Tatton-Brown, Katrina, Verbeek, Nienke E, van Hirtum-Das, Michele, Breckpot, Jeroen, Hammer, Trine Bjørg, Møller, Rikke S, Whitney, Andrea, Douglas, Andrew G L, Kharbanda, Mira, Brunetti-Pierri, Nicola, Morleo, Manuela, Nigro, Vincenzo, May, Halie J, Tao, James X, Argili, Emanuela, Sherr, Elliot H, Dobyns, William B, Consortium, Genomics England Research, Baines, Richard A, Warwicker, Jim, Parker, J Alex, Banka, Siddharth, Campeau, Philippe M, and Escayg, Andrew

Subjects
neurodevelopmental disorders, ATP6V0C, VMA3, epilepsy genetic, V-ATPase
Abstract

The vacuolar H+-ATPase (V-ATPase) is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the V-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modeling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased V-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behavior, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction, and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder, and provides insight into disease mechanisms.

Published
2022

9. Contributors

Author

Aaen, Gregory S., Abend, Nicholas Scott, Abou-Hamden, Amal, Allen, Jeffrey C., Amato, Anthony A., Amlie-Lefond, Catherine, Ashwal, Stephen, Bailey, Russell C., Bale, James F., Jr., Banwell, Brenda, Barañano, Kristin W., Barkovich, A. James, Barohn, Richard J., Bartels, Ute K., Bartnik-Olson, Brenda, Barzilai, Ori, Bassuk, Alexander, Bearden, David R., Ben-Sira, Liat, Bernard, Timothy J., Berry-Kravis, Elizabeth, Beslow, Lauren A., Biegel, Jaclyn A., Billinghurst, Lori, Birnbaum, Angela K., Blackburn, Joanna S., Bobowski, Nuala, Boire, Adrienne, Bönnemann, Carsten G., Bonifacio, Sonia L., Bonthius, Daniel J., Borcherding, Breck, Branchford, Brian R., Brandsema, John, Brennan, Kathryn M., Brenton, J. Nicholas, Brooks-Kayal, Amy R., Brown, Lawrence W., Buchalter, Jeffrey, Camfield, Carol S., Camfield, Peter R., Campoy, Cristina, Carpenter, Jessica L., Chang, Taeun, Chau, Vann, Chi, Susan N., Chiriboga, Claudia A., Cho, Yoon-Jae, Christian, Cindy W., Chrestian, Nicholas, Cilio, Maria Roberta, Clark, Robin D., Cohen, Bruce H., Cohn, Ronald D., Connolly, Anne M., Constable, Todd, Constantini, Shlomi, Conway, Jeannine M., Coulter, David L., Cowan, Tina M., Dale, Russell C., Darbro, Benjamin, Darras, Basil T., Dastgir, Jahannaz, De Meirleir, Linda, De Vivo, Darryl C., de Vries, Linda S., Deisch, Jeremy K., Deltenre, Paul, Desai, Jay, Descartes, Maria, deVeber, Gabrielle, Dhamne, Sameer C., Diaz, Jullianne, DiMauro, Salvatore, Dobyns, William B., Doherty, Dan, Donner, Elizabeth J., Dosenbach, Nico U.F., Dowling, James J., Drake, James M., Ejerskov, Cecile, Engel, Andrew G., Enns, Gregory M., Escolano-Margarit, María Victoria, Etzion, Iris, Fatemi, S. Ali, Fehlings, Darcy L., Feinberg, Michelle Lauren, Ferriero, Donna M., Filipek, Pauline A., Finkel, Richard S., Fisher, Paul G., Flanigan, Kevin, Foreman, Nicholas K., Franco, Israel, Frank, Yitzchak, Fredrick, Douglas R., Freeze, Hudson H., Fuente-Mora, Cristina, Furman, Joseph M., Gallagher, Renata C., Garel, Catherine, Gertsch, Emily, Gilbert, Donald L., Gilles, Elizabeth E., Giza, Christopher C., Glaser, Carol A., Glass, Hannah C., Glauser, Tracy, Glykys, Joseph, Goldstein, Amy, Gonorazky, Hernan Dario, Gonzalez, Rodolfo, Goodkin, Howard P., Graham, John M., Jr., Greninger, Alexander L., Gronseth, Gary, Gropman, Andrea L., Grundy, Richard, Guerrini, Renzo, Gupta, Nalin, Hahn, Jin S., Hamblin, Milton H., Hani, Abeer J., Hanmantgad, Sharyu, Harbert, Mary J., Harini, Chellamani, Harriott, Andrea M., Heatwole, Chad, Hershey, Andrew D., Hirtz, Deborah G., Holmes, Gregory L., Holshouser, Barbara A., Hurwitz, Kathleen A., Hwang, Eugene, Ichord, Rebecca N., Jafar-Nejad, Paymaan, Jain, Sejal V., Jordan, Lori, Kabbouche, Marielle A., Kacperski, Joanne, Kang, Peter B., Kariannis, Matthias A., Kaufmann, Horacio, Kaye, Harper L., Keating, Robert, Kennedy, Colin R., Khakoo, Yasmin, Kirton, Adam, Kissel, John T., Knupp, Kelly G., Korf, Bruce R., Kossoff, Eric H., Kothare, Sanjeev V., Kupfer, Oren, LaFrance, W. Curt, Jr., Latal, Beatrice, Leber, Steven M., Lee, Jean-Pyo, Leppik, Ilo E., Lerman-Sagie, Tally, Lerner, Jason T., Leventer, Richard J., Licht, Daniel J., Lichter-Konecki, Uta, Lidar, Zvi, Liem, Djin Gie, Loddenkemper, Tobias, Long, Roger K., Luc, Quyen N., Mackay, Mark, Majnemer, Annette, Makhani, Naila, Malinger, Gustavo, Mandelbaum, David E., Maricich, Stephen M., Maski, Kiran P., Mathur, Mudit, Matthews, Dennis J., McMahon, Kelly, DeMara-Hoth, Megan B., Mendelsohn, Bryce, Mennella, Julie A., Ment, Laura R., Mercuri, Eugenio, Michelson, David J., Mikati, Mohamad A., Mikhail, Fady M., Miller, Steven Paul, Milunsky, Jeff M., Mink, Jonathan W., Mirzaa, Ghayda M., Mitchell, Wendy G., Mohan, Michael A., Mohassel, Payam, Moharir, Mahendranath, Monani, Umrao R., Monje Deisseroth, Michelle, Moodley, Manikum, Mower, Andrew, Moxley, Richard T., III, Mueller, Sabine, Muotri, Alysson R., Nagamani, Sandesh C.S., Narayanan, Mohan J., Narayanan, Vinodh, Nass, Ruth D., Neul, Jeffrey L., Nevo, Yoram, Ng, Bobby G., Nickels, Katherine C., Nimmo, Graeme A.M., Noetzel, Michael J., Norcliffe-Kaufmann, Lucy, Nordli, Douglas R., Jr., Nowak-Göttl, Ulrike, O'Brien, Hope L., Oleszek, Joyce, Oskoui, Maryam, Paciorkowski, Alex R., Packer, Roger J., Packman, Seymour, Palma, Jose-Alberto, Pardo, Andrea C., Parsons, Julie A., Partridge, John Colin, Pastores, Gregory M., Patterson, Marc C., Pearce, William J., Pearl, Phillip L., Penner, Melanie, Percival, Leila, Pereira, Marcia, Pfister, Stefan M., Phillips, John, Plecko, Barbara, Plioplys, Sigita, Poduri, Annapurna, Poisson, Sharon, Pomeroy, Scott L., Poretti, Andrea, Powers, Scott W., Pranzatelli, Michael R., Przekop, Allison, Rabie, Malcolm, Rangasamy, Sampathkumar, Raymond, Gerald V., Reddy, Alyssa T., Rendleman, Rebecca L., Rho, Jong M., Rodan, Lance H., Roddy, Sarah M., Rogers, Elizabeth E., Rosenthal, Stephen M., Rosman, N. Paul, Ross, M. Elizabeth, Rotenberg, Alexander, Rust, Robert S., Sanchez, Cheryl P., Sanchez, Pedro, Sánchez Fernández, Iván, Sands, Tristan T., Sanger, Terence D., Sannagowdara, Kumar, Scheinost, Dustin, Scher, Mark S., Schor, Nina F., Schrauwen, Isabelle, Segal, Michael M., Seinfeld, Syndi, Selcen, Duygu, Seltzer, Laurie E., Semrud-Clikeman, Margaret, Shaw, Dennis W., Shaywitz, Bennett A., Shaywitz, Sally E., Shellhaas, Renée A., Sherr, Elliott H., Sheth, Rita D., Shevell, Michael I., Shinnar, Shlomo, Shofty, Ben, Shu, Stanford K., Shy, Michael E., Silveira Moriyama, Laura, Silvestri, Nicholas J., Sims, Katherine B., Singer, Harvey S., Singhal, Nilika Shah, Smith, Craig M., Smith, Edward, Smith, Stephen A., Snyder, Evan Y., Soul, Janet, Spalink, Christy L., Spencer, Karen A., Stafstrom, Carl E., Steinfeld, Robert, Strober, Jonathan B., Sullivan, Joseph, Swaiman, Kenneth F., Swoboda, Kathryn J., Tate, Elizabeth D., Tatum, William O., IV, Tein, Ingrid, Tekulve, Kristyn, Tenney, Jeffrey R., Thiele, Elizabeth A., Thompson-Stone, Robert, Tochen, Laura, Tormoehlen, Laura M., Tran, Lily, Trauner, Doris A., Turnacioglu, Sinan O., Ullrich, Nicole J., Urion, David K., Van Camp, Guy, Van Hirtum-Das, Michèle, van Karnebeek, Clara D.M., Van Maldergem, Lionel, Vanderver, Adeline, Vitanza, Nicholas A., von Rhein, Michael, von Scheven, Emily, Wagner, Ann, Wainwright, Mark S., Walker, Melissa A., Walkup, John T., Walsh, Laurence, Walters-Sen, Lauren C., Wang, Raymond Y., Warner, Thomas T., Whelan, Harry T., Weinberg, Geoffrey A., Wells, Elizabeth M., Wheless, James W., Wirrell, Elaine C., Wisoff, Jeffrey H., Wolf, Nicole I., Wolfe, Gil I., Wright, F. Virginia, Wycliffe, Nathaniel D., Yang, Michele L., Yuskaitis, Christopher J., Zoghbi, Huda Y., and Zupanc, Mary L.

Published
2017
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10. Minipterional craniotomy for resection of epileptogenic cavernous malformation.

Author

Chartrain A, Bullis C, Sader N, Chiarelli PA, Kahan M, Jordan B, Agurs L, Van Hirtum-Das M, Yuliati A, Joshi S, and Chu J

Abstract

Epilepsy is a common symptom of pediatric cavernous malformations. In medically refractory patients, surgery can achieve high seizure freedom rates with low morbidity. This video depicts the use of a minipterional craniotomy and transsulcal resection of a frontal opercular cavernous malformation in a 13-year-old female with medically intractable epilepsy. At 1-year follow-up, she was evaluated as Engel class I with a significant improvement in her quality of life. Principles of cavernous malformation resection for the treatment of epilepsy are also reviewed. The video can be found here: https://stream.cadmore.media/r10.3171/2024.4.FOCVID2441., Competing Interests: Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this publication.The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this publication., (© 2024, The Authors.)

Published
2024
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11. ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy.

Author

Mattison KA, Tossing G, Mulroe F, Simmons C, Butler KM, Schreiber A, Alsadah A, Neilson DE, Naess K, Wedell A, Wredenberg A, Sorlin A, McCann E, Burghel GJ, Menendez B, Hoganson GE, Botto LD, Filloux FM, Aledo-Serrano Á, Gil-Nagel A, Tatton-Brown K, Verbeek NE, van der Zwaag B, Aleck KA, Fazenbaker AC, Balciuniene J, Dubbs HA, Marsh ED, Garber K, Ek J, Duno M, Hoei-Hansen CE, Deardorff MA, Raca G, Quindipan C, van Hirtum-Das M, Breckpot J, Hammer TB, Møller RS, Whitney A, Douglas AGL, Kharbanda M, Brunetti-Pierri N, Morleo M, Nigro V, May HJ, Tao JX, Argilli E, Sherr EH, Dobyns WB, Baines RA, Warwicker J, Parker JA, Banka S, Campeau PM, and Escayg A

Subjects
Humans, Saccharomyces cerevisiae genetics, Saccharomyces cerevisiae metabolism, Adenosine Triphosphate, Vacuolar Proton-Translocating ATPases genetics, Vacuolar Proton-Translocating ATPases metabolism, Epilepsy genetics
Abstract

The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Published
2023
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