{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T04:18:07Z","timestamp":1768623487393,"version":"3.49.0"},"reference-count":38,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,7,27]],"date-time":"2023-07-27T00:00:00Z","timestamp":1690416000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["RN324373"],"award-info":[{"award-number":["RN324373"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>The vacuolar H+-ATPase is a multisubunit enzyme which plays an essential role in the acidification and functions of lysosomes, endosomes, and synaptic vesicles. Many genes encoding subunits of V-ATPases, namely ATP6V0C, ATP6V1A, ATP6V0A1, and ATP6V1B2, have been associated with neurodevelopmental disorders and epilepsy. The autosomal dominant ATP6V1B2 p.Arg506* variant can cause both congenital deafness with onychodystrophy, autosomal dominant (DDOD) and deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures syndromes (DOORS). Some but not all individuals with this truncating variant have intellectual disability and\/or epilepsy, suggesting incomplete penetrance and\/or variable expressivity. To further explore the impact of the p.Arg506* variant in neurodevelopment and epilepsy, we generated Atp6v1b2emR506* mutant mice and performed standardized phenotyping using the International Mouse Phenotyping Consortium (IMPC) pipeline. In addition, we assessed the EEG profile and seizure susceptibility of Atp6v1b2emR506* mice. Behavioral tests revealed that the mice present locomotor hyperactivity and show less anxiety-associated behaviors. Moreover, EEG analyses indicate that Atp6v1b2emR506* mutant mice have interictal epileptic activity and that both heterozygous (like patients) and homozygous mice have reduced seizure thresholds to pentylenetetrazol. Our results confirm that variants in ATP6V1B2 can cause seizures and that the Atp6v1b2emR506* heterozygous mouse model is a valuable tool to further explore the pathophysiology and potential treatments for vacuolar ATPases-associated epilepsy and disorders.<\/jats:p>","DOI":"10.3390\/genes14081538","type":"journal-article","created":{"date-parts":[[2023,7,28]],"date-time":"2023-07-28T01:56:16Z","timestamp":1690509376000},"page":"1538","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The ATP6V1B2 DDOD\/DOORS-Associated p.Arg506* Variant Causes Hyperactivity and Seizures in Mice"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3554-2673","authenticated-orcid":false,"given":"Justine","family":"Rousseau","sequence":"first","affiliation":[{"name":"CHU Sainte-Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel Boris","family":"Tene Tadoum","sequence":"additional","affiliation":[{"name":"CHU Sainte-Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marisol","family":"Lavertu Jolin","sequence":"additional","affiliation":[{"name":"CHU Sainte-Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thi Tuyet Mai","family":"Nguyen","sequence":"additional","affiliation":[{"name":"CHU Sainte-Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norbert Fonya","family":"Ajeawung","sequence":"additional","affiliation":[{"name":"CHU Sainte-Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1892-6154","authenticated-orcid":false,"given":"Ann M.","family":"Flenniken","sequence":"additional","affiliation":[{"name":"Lunenfeld-Tanenbaum Research Institute, The Centre for Phenogenomics, Toronto, ON M5T 3H7, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9619-146X","authenticated-orcid":false,"given":"Lauryl M. J.","family":"Nutter","sequence":"additional","affiliation":[{"name":"The Hospital for Sick Children, The Centre for Phenogenomics, Toronto, ON M5T 3H7, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Igor","family":"Vukobradovic","sequence":"additional","affiliation":[{"name":"Lunenfeld-Tanenbaum Research Institute, The Centre for Phenogenomics, Toronto, ON M5T 3H7, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elsa","family":"Rossignol","sequence":"additional","affiliation":[{"name":"CHU Sainte-Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philippe M.","family":"Campeau","sequence":"additional","affiliation":[{"name":"CHU Sainte-Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1146\/annurev-genom-120219-074937","article-title":"The Genetics of Epilepsy","volume":"21","author":"Perucca","year":"2020","journal-title":"Annu. 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