{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T12:29:12Z","timestamp":1789129752161,"version":"build-2803163510"},"reference-count":0,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Developmental delay and seizures with or without movement abnormalities (OMIM 617836) caused by heterozygous pathogenic variants in the DHDDS gene (DHDDS-CDG) is a rare genetic disease that belongs to the progressive encephalopathy spectrum. It results in cognitive delay in affected children, accompanied by myoclonus, seizures, ataxia and tremor, which worsens over time. DHDDS encodes a subunit of a DHDDS\/NUS1 cis-prenyltransferase (cis-PTase), a branch point enzyme of the mevalonate pathway essential for N-linked glycosylation.<\/jats:p>\n                  <jats:p>We describe the first mouse model of this disease, DhddsR37H+\/- strain, heterozygous for the human recurrent de novo c.110G&amp;gt;A:p.R37H pathogenic variant. DhddsR37H+\/- mice present with seizures, myoclonus and memory deficits associated with reduced density or\/and maturity of inhibitory interneurons in the cortex. Multiomics analyses of mouse CNS tissues, together with the enzymatic\/structural characterization of the R37H DHDDS mutant protein, reveal that the variant produces a catalytically inactive enzyme and results in a brain dolichol deficit, aberrant glycosylation of brain glycoproteins, including those involved in synaptic transmission and major perturbations in the CNS proteome and lipidome. Acetazolamide, a carbonic anhydrase inhibitor clinically approved for treatment of glaucoma, epilepsy, and intracranial hypertension, and successfully used \u201coff-label\u201d to treat genetic movement disorders, reduces seizure susceptibility to pentylenetetrazol in DhddsR37H+\/- mice, suggesting potential therapeutic value of using this drug in human DHDDS-CDG patients.<\/jats:p>\n                  <jats:p>Together, our results define cis-PTase as a master regulator of CNS development and function and establish that its monoallelic debilitating variants cause a novel congenital disorder of glycosylation associated with aberrant levels of neuronal proteins and lipids.<\/jats:p>","DOI":"10.1093\/brain\/awag304","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T11:28:51Z","timestamp":1789126131000},"source":"Crossref","is-referenced-by-count":0,"title":["Mice with the mono-allelic p.R37H\n                    <i>Dhdds<\/i>\n                    variant show aberrant glycosylation and interneuron deficits"],"prefix":"10.1093","author":[{"given":"Afitz","family":"Da Silva","sequence":"first","affiliation":[{"name":"CHU Ste-Justine, Department of Paediatrics, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, H3T 1C5, QC ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merrick S","family":"Fallah","sequence":"additional","affiliation":[{"name":"CHU Ste-Justine, Department of Paediatrics, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, H3T 1C5, QC ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel Boris","family":"Tene Tadoum","sequence":"additional","affiliation":[{"name":"CHU Ste-Justine, Department of Paediatrics, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, H3T 1C5, QC ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehrnaz","family":"Fazeli","sequence":"additional","affiliation":[{"name":"CHU Ste-Justine, Department of Paediatrics, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, H3T 1C5, QC ,","place":["Canada"]},{"name":"Department of Anatomy and Cell Biology, McGill University , Montreal, H3A 0C7, QC ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irena J J","family":"Muffels","sequence":"additional","affiliation":[{"name":"Department of Genetic and Genomic Sciences, Icahn School of Medicine at Mount Sinai , New York, NY 10029 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyan","family":"Wang","sequence":"additional","affiliation":[{"name":"CHU Ste-Justine, Department of Paediatrics, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, H3T 1C5, QC ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francois","family":"Grenier","sequence":"additional","affiliation":[{"name":"CHU Ste-Justine, Department of Paediatrics, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, H3T 1C5, QC ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohit","family":"Budhraja","sequence":"additional","affiliation":[{"name":"Department of Genetic and Genomic Sciences, Icahn School of Medicine at Mount Sinai , New York, NY 10029 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Sturiale","sequence":"additional","affiliation":[{"name":"CNR Institute for Polymers, Composites and Biomaterials , Catania, 95126 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Messina","sequence":"additional","affiliation":[{"name":"CNR Institute for Polymers, Composites and Biomaterials , Catania, 95126 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moshe","family":"Giladi","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Gray Faculty of Medical and Health Sciences, Tel Aviv University , 69978 ,","place":["Israel"]},{"name":"Department of Internal Medicine D, Tel Aviv Sourasky Medical Center , Tel Aviv, 64239 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahsa","family":"Taherzadeh","sequence":"additional","affiliation":[{"name":"CHU Ste-Justine, Department of Paediatrics, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, H3T 1C5, QC ,","place":["Canada"]},{"name":"Department of Anatomy and Cell Biology, McGill University , Montreal, H3A 0C7, QC ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c9ric","family":"Bonneil","sequence":"additional","affiliation":[{"name":"Institute for Research in Immunology and Cancer, University of Montreal , Montreal, H3T 1J4, QC ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaukat","family":"Khan","sequence":"additional","affiliation":[{"name":"Nemours\/Alfred I. duPont Hospital for Children , Wilmington, DE 19803 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle te","family":"Vruchte","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Oxford , Oxford, OX1 3QT ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1483-8691","authenticated-orcid":false,"given":"Yojiro","family":"Yamanaka","sequence":"additional","affiliation":[{"name":"McGill University Transgenic Core facility, McGill University , Montreal, H3G OB1, QC ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graziella","family":"Di Cristo","sequence":"additional","affiliation":[{"name":"CHU Ste-Justine, Department of Paediatrics, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, H3T 1C5, QC ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fadi F","family":"Hamdan","sequence":"additional","affiliation":[{"name":"CHU Ste-Justine, Department of Paediatrics, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, H3T 1C5, QC ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7614-0403","authenticated-orcid":false,"given":"Frances M","family":"Platt","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Oxford , Oxford, OX1 3QT ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunji","family":"Tomatsu","sequence":"additional","affiliation":[{"name":"Nemours\/Alfred I. duPont Hospital for Children , Wilmington, DE 19803 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoni","family":"Haitin","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Gray Faculty of Medical and Health Sciences, Tel Aviv University , 69978 ,","place":["Israel"]},{"name":"Sagol School of Neuroscience, Tel Aviv University , Tel Aviv, 6997801 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6915-4364","authenticated-orcid":false,"given":"Tamas","family":"Kozicz","sequence":"additional","affiliation":[{"name":"Department of Genetic and Genomic Sciences, Icahn School of Medicine at Mount Sinai , New York, NY 10029 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Thibault","sequence":"additional","affiliation":[{"name":"Institute for Research in Immunology and Cancer, University of Montreal , Montreal, H3T 1J4, QC ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Garozzo","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, McGill University , Montreal, H3A 0C7, QC ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9943-6127","authenticated-orcid":false,"given":"Akilesh","family":"Pandey","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, Mayo Clinic , Rochester, MN 55905 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Morava","sequence":"additional","affiliation":[{"name":"Department of Genetic and Genomic Sciences, Icahn School of Medicine at Mount Sinai , New York, NY 10029 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elsa","family":"Rossignol","sequence":"additional","affiliation":[{"name":"CHU Ste-Justine, Department of Paediatrics, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, H3T 1C5, QC ,","place":["Canada"]},{"name":"Department of Neurosciences, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, H3T 1J4, QC ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6612-1062","authenticated-orcid":false,"given":"Alexey V","family":"Pshezhetsky","sequence":"additional","affiliation":[{"name":"CHU Ste-Justine, Department of Paediatrics, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, H3T 1C5, QC ,","place":["Canada"]},{"name":"Department of Anatomy and Cell Biology, McGill University , Montreal, H3A 0C7, QC ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,9,11]]},"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awag304\/71031253\/awag304.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awag304\/71031253\/awag304.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T11:28:51Z","timestamp":1789126131000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/advance-article\/doi\/10.1093\/brain\/awag304\/8790444"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,11]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1093\/brain\/awag304","relation":{},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,11]]},"article-number":"awag304"}}