{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T20:03:01Z","timestamp":1790798581490,"version":"4.1.0"},"posted":{"date-parts":[[2025,6,3]]},"group-title":"Neuroscience","reference-count":49,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T00:00:00Z","timestamp":1748908800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["K08NS118119"],"award-info":[{"award-number":["K08NS118119"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01NS102731"],"award-info":[{"award-number":["R01NS102731"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R21NS112742"],"award-info":[{"award-number":["R21NS112742"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["U54NS115198"],"award-info":[{"award-number":["U54NS115198"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Amour Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,6,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Congenital disorders of glycosylation (CDG) are a group of neurogenetic conditions resulting from disruptions in the cellular glycosylation machinery. The majority of CDG patients have compound heterozygous pathogenic variants in the phosphomannomutase 2 (\n                  <jats:italic>PMM2)<\/jats:italic>\n                  gene. Individuals with PMM2-CDG exhibit multi-systemic symptoms, prominently featuring neurological deficits with nearly all patients exhibiting cerebellar hypoplasia and ataxia. To overcome embryonic lethality caused by whole body knock-out of\n                  <jats:italic>Pmm2<\/jats:italic>\n                  and mimic patient-related compound heterozygous pathogenic variants, we paired a\n                  <jats:italic>Pmm2<\/jats:italic>\n                  flox allele (\n                  <jats:italic>Pmm2<\/jats:italic>\n                  <jats:sup>fl<\/jats:sup>\n                  ) with a catalytically inactive knock-in allele (\n                  <jats:italic>Pmm2<\/jats:italic>\n                  <jats:sup>R137H<\/jats:sup>\n                  ), commonly present in PMM2-CDG patients. Mice with post-mitotic loss of PMM2 from neurons or astrocytes are indistinguishable from unaffected littermates, including in a broad battery of neurological assessments. In contrast, removal of PMM2 from embryonic neural precursor cells leads to cerebellar hypoplasia, ataxia, seizures, and early lethality. Comprehensive multi-omics profiling, including metabolomics, glycomics, single-cell transcriptomics, proteomics, and glycoproteomics, reveal widespread molecular disturbances throughout the brain, with the cerebellum showing the most pronounced disruption. These findings highlight the heightened dependency of the developing cerebellum on intact N-glycosylation, aligning with clinical observations in PMM2-CDG patients. Importantly, glycoproteomic alterations identified in our mouse model are corroborated in PMM2-CDG patient post-mortem cerebellar tissue, underscoring the translational relevance of our findings and implicating impaired synaptic transmission as a key pathogenic mechanism.\n                <\/jats:p>","DOI":"10.1101\/2025.06.01.657261","type":"posted-content","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T05:30:32Z","timestamp":1749015032000},"source":"Crossref","is-referenced-by-count":2,"title":["Novel mouse model reveals neurodevelopmental origin of PMM2-CDG brain pathology"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0313-0743","authenticated-orcid":false,"given":"Andrew C.","family":"Edmondson","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Division of Human Genetics, The Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA"},{"name":"Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohit","family":"Budhraja","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zijie","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Melendez-Perez","sequence":"additional","affiliation":[{"name":"Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cadmus","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Human Genetics, The Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA"},{"name":"Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Radenkovic","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics, Mayo Clinic, Rochester MN, USA"},{"name":"Department of Genetics, Section Metabolic Diagnostics, UMC Utrecht, Utrecht, NL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley M.","family":"Collins","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Human Genetics, The Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily J.","family":"Shiplett","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Human Genetics, The Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA"},{"name":"Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8331-9812","authenticated-orcid":false,"given":"Sophie F.","family":"Hill","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neurology, The Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ala","family":"Somarowthu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neurology, The Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Dam","sequence":"additional","affiliation":[{"name":"Department of Neural Sciences, Center for Neural Development and Repair, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling-Lin","family":"Pai","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, The Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariarita","family":"Santi","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, The Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seonhee","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Neural Sciences, Center for Neural Development and Repair, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"He","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, The Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ethan M.","family":"Goldberg","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neurology, The Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA"},{"name":"Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA"},{"name":"Department of Neuroscience, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamas","family":"Kozicz","sequence":"additional","affiliation":[{"name":"Department of Genomics and Genetic Sciences, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Morava","sequence":"additional","affiliation":[{"name":"Department of Genomics and Genetic Sciences, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akhilesh","family":"Pandey","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaolan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041201031426000_2025.06.01.657261v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5200470"},{"key":"2026041201031426000_2025.06.01.657261v1.2","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12024"},{"key":"2026041201031426000_2025.06.01.657261v1.3","unstructured":"Sparks, S.E. , and Krasnewich, D.M. (1993). PMM2-CDG (CDG-Ia). In GeneReviews((R)), M.P. Adam , H.H. Ardinger , R.A. Pagon , S.E. Wallace , L.J.H. Bean , K. Stephens , and A. Amemiya , eds."},{"key":"2026041201031426000_2025.06.01.657261v1.4","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2017-104903"},{"key":"2026041201031426000_2025.06.01.657261v1.5","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-015-0358-y"},{"key":"2026041201031426000_2025.06.01.657261v1.6","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-004-0975-3"},{"key":"2026041201031426000_2025.06.01.657261v1.7","doi-asserted-by":"publisher","DOI":"10.1007\/s002470050571"},{"key":"2026041201031426000_2025.06.01.657261v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2018.03.002"},{"key":"2026041201031426000_2025.06.01.657261v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.113883"},{"key":"2026041201031426000_2025.06.01.657261v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.114976"},{"key":"2026041201031426000_2025.06.01.657261v1.11","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26245"},{"key":"2026041201031426000_2025.06.01.657261v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2023.101056"},{"key":"2026041201031426000_2025.06.01.657261v1.13","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddw085"},{"key":"2026041201031426000_2025.06.01.657261v1.14","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.02391-05"},{"key":"2026041201031426000_2025.06.01.657261v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2548"},{"key":"2026041201031426000_2025.06.01.657261v1.16","doi-asserted-by":"publisher","DOI":"10.1093\/bfgp\/elm022"},{"key":"2026041201031426000_2025.06.01.657261v1.17","doi-asserted-by":"publisher","DOI":"10.3389\/fncir.2014.00076"},{"key":"2026041201031426000_2025.06.01.657261v1.18","doi-asserted-by":"publisher","DOI":"10.12688\/wellcomeopenres.17965.1"},{"key":"2026041201031426000_2025.06.01.657261v1.19","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3095-08.2009"},{"key":"2026041201031426000_2025.06.01.657261v1.20","doi-asserted-by":"publisher","DOI":"10.1038\/12703"},{"key":"2026041201031426000_2025.06.01.657261v1.21","doi-asserted-by":"publisher","DOI":"10.1007\/s00335-019-09804-5"},{"key":"2026041201031426000_2025.06.01.657261v1.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2020.01.008"},{"key":"2026041201031426000_2025.06.01.657261v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(95)01357-1"},{"key":"2026041201031426000_2025.06.01.657261v1.24","doi-asserted-by":"publisher","DOI":"10.1042\/bj3390201"},{"key":"2026041201031426000_2025.06.01.657261v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2017.11.012"},{"key":"2026041201031426000_2025.06.01.657261v1.26","doi-asserted-by":"publisher","DOI":"10.1093\/clinchem\/hvac012"},{"key":"2026041201031426000_2025.06.01.657261v1.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.tice.2022.101897"},{"key":"2026041201031426000_2025.06.01.657261v1.28","doi-asserted-by":"publisher","DOI":"10.1242\/bio.20122287"},{"key":"2026041201031426000_2025.06.01.657261v1.29","doi-asserted-by":"publisher","DOI":"10.1038\/s41434-025-00525-w"},{"key":"2026041201031426000_2025.06.01.657261v1.30","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-020-01630-2"},{"key":"2026041201031426000_2025.06.01.657261v1.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2024.108509"},{"key":"2026041201031426000_2025.06.01.657261v1.32","doi-asserted-by":"publisher","DOI":"10.1002\/cld.1105"},{"key":"2026041201031426000_2025.06.01.657261v1.33","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2016121312"},{"key":"2026041201031426000_2025.06.01.657261v1.34","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2017.58"},{"key":"2026041201031426000_2025.06.01.657261v1.35","doi-asserted-by":"publisher","DOI":"10.1515\/jpem-2020-0168"},{"key":"2026041201031426000_2025.06.01.657261v1.36","doi-asserted-by":"publisher","DOI":"10.17925\/EE.2020.16.1.66"},{"key":"2026041201031426000_2025.06.01.657261v1.37","doi-asserted-by":"publisher","DOI":"10.1007\/s00467-021-04953-9"},{"key":"2026041201031426000_2025.06.01.657261v1.38","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.1674"},{"key":"2026041201031426000_2025.06.01.657261v1.39","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-023-02523-7"},{"key":"2026041201031426000_2025.06.01.657261v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.neo.2022.100846"},{"key":"2026041201031426000_2025.06.01.657261v1.41","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019"},{"key":"2026041201031426000_2025.06.01.657261v1.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2023.101389"},{"key":"2026041201031426000_2025.06.01.657261v1.43","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2018.296780"},{"key":"2026041201031426000_2025.06.01.657261v1.44","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-023-01943-7"},{"key":"2026041201031426000_2025.06.01.657261v1.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.05.031"},{"key":"2026041201031426000_2025.06.01.657261v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2018.11.005"},{"key":"2026041201031426000_2025.06.01.657261v1.47","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03500-8"},{"key":"2026041201031426000_2025.06.01.657261v1.48","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03220-z"},{"key":"2026041201031426000_2025.06.01.657261v1.49","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.06.01.657261","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T08:03:25Z","timestamp":1775981005000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.06.01.657261"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,3]]},"references-count":49,"URL":"https:\/\/doi.org\/10.1101\/2025.06.01.657261","relation":{},"subject":[],"published":{"date-parts":[[2025,6,3]]},"subtype":"preprint"}}