{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T02:33:29Z","timestamp":1780108409410,"version":"3.54.0"},"reference-count":79,"publisher":"Oxford University Press (OUP)","issue":"24","license":[{"start":{"date-parts":[[2022,7,31]],"date-time":"2022-07-31T00:00:00Z","timestamp":1659225600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Fondazione Centro San Raffaele"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,12,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Mutations in the Myelin Protein Zero gene (MPZ), encoding P0, the major structural glycoprotein of peripheral nerve myelin, are the cause of Charcot\u2013Marie-Tooth (CMT) type 1B neuropathy, and most P0 mutations appear to act through gain-of-function mechanisms. Here, we investigated how misglycosylation, a pathomechanism encompassing several genetic disorders, may affect P0 function. Using in vitro assays, we showed that gain of glycosylation is more damaging for P0 trafficking and functionality as compared with a loss of glycosylation. Hence, we generated, via CRISPR\/Cas9, a mouse model carrying the MPZD61N mutation, predicted to generate a new N-glycosylation site in P0. In humans, MPZD61N causes a severe early-onset form of CMT1B, suggesting that hyperglycosylation may interfere with myelin formation, leading to pathology. We show here that MPZD61N\/+ mice develop a tremor as early as P15 which worsens with age and correlates with a significant motor impairment, reduced muscular strength and substantial alterations in neurophysiology. The pathological analysis confirmed a dysmyelinating phenotype characterized by diffuse hypomyelination and focal hypermyelination. We find that the mutant P0D61N does not cause significant endoplasmic reticulum stress, a common pathomechanism in CMT1B, but is properly trafficked to myelin where it causes myelin uncompaction. Finally, we show that myelinating dorsal root ganglia cultures from MPZD61N mice replicate some of the abnormalities seen in vivo, suggesting that they may represent a valuable tool to investigate therapeutic approaches. Collectively, our data indicate that the MPZD61N\/+ mouse represents an authentic model of severe CMT1B affirming gain-of-glycosylation in P0 as a novel pathomechanism of disease.<\/jats:p>","DOI":"10.1093\/hmg\/ddac170","type":"journal-article","created":{"date-parts":[[2022,7,31]],"date-time":"2022-07-31T18:19:55Z","timestamp":1659291595000},"page":"4255-4274","source":"Crossref","is-referenced-by-count":12,"title":["A novel mouse model of CMT1B identifies hyperglycosylation as a new pathogenetic mechanism"],"prefix":"10.1093","volume":"31","author":[{"given":"Francesca A","family":"Veneri","sequence":"first","affiliation":[{"name":"Biology of Myelin Unit , Division of Genetics and Cell Biology, , 20132 Milan , Italy"},{"name":"IRCCS Ospedale San Raffaele , Division of Genetics and Cell Biology, , 20132 Milan , Italy"},{"name":"Department of Neuroscience , Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), , 16132 Genova , Italy"},{"name":"University of Genova, IRCCS AOU San Martino-IST , Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), , 16132 Genova , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Prada","sequence":"additional","affiliation":[{"name":"Department of Neuroscience , Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), , 16132 Genova , Italy"},{"name":"University of Genova, IRCCS AOU San Martino-IST , Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), , 16132 Genova , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Mastrangelo","sequence":"additional","affiliation":[{"name":"Biology of Myelin Unit , Division of Genetics and Cell Biology, , 20132 Milan , Italy"},{"name":"IRCCS Ospedale San Raffaele , Division of Genetics and Cell Biology, , 20132 Milan , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cinzia","family":"Ferri","sequence":"additional","affiliation":[{"name":"Biology of Myelin Unit , Division of Genetics and Cell Biology, , 20132 Milan , Italy"},{"name":"IRCCS Ospedale San Raffaele , Division of Genetics and Cell Biology, , 20132 Milan , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucilla","family":"Nobbio","sequence":"additional","affiliation":[{"name":"Department of Neuroscience , Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), , 16132 Genova , Italy"},{"name":"University of Genova, IRCCS AOU San Martino-IST , Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), , 16132 Genova , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Passalacqua","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Genova , 16132 Genova , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1902-1544","authenticated-orcid":false,"given":"Maria","family":"Milanesi","sequence":"additional","affiliation":[{"name":"Experimental Oncology and Immunology , Department of Molecular and Translational Medicine, , 25123 Brescia , Italy"},{"name":"University of Brescia , Department of Molecular and Translational Medicine, , 25123 Brescia , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Bianchi","sequence":"additional","affiliation":[{"name":"Movement Disorders Unit , Division of Neuroscience, , 20132 Milan , Italy"},{"name":"IRCCS Ospedale San Raffaele , Division of Neuroscience, , 20132 Milan , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ubaldo","family":"Del Carro","sequence":"additional","affiliation":[{"name":"Movement Disorders Unit , Division of Neuroscience, , 20132 Milan , Italy"},{"name":"IRCCS Ospedale San Raffaele , Division of Neuroscience, , 20132 Milan , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Michel","family":"Vallat","sequence":"additional","affiliation":[{"name":"Department and Laboratory of Neurology , National Reference Center for \u2018Rare Peripheral Neuropathies\u2019, , 87000 Limoges , France"},{"name":"University Hospital of Limoges (CHU Limoges), Dupuytren Hospital , National Reference Center for \u2018Rare Peripheral Neuropathies\u2019, , 87000 Limoges , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phu","family":"Duong","sequence":"additional","affiliation":[{"name":"Department of Comparative Biosciences , School of Veterinary Medicine, , Madison, WI 53706 , USA"},{"name":"University of Wisconsin\u2013Madison , School of Veterinary Medicine, , Madison, WI 53706 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Svaren","sequence":"additional","affiliation":[{"name":"Department of Comparative Biosciences , School of Veterinary Medicine, , Madison, WI 53706 , USA"},{"name":"University of Wisconsin\u2013Madison , School of Veterinary Medicine, , Madison, WI 53706 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelo","family":"Schenone","sequence":"additional","affiliation":[{"name":"Department of Neuroscience , Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), , 16132 Genova , Italy"},{"name":"University of Genova, IRCCS AOU San Martino-IST , Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), , 16132 Genova , Italy"},{"name":"Department of Neurology, IRCCS Ospedale Policlinico San Martino , 16132 Genova , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Grandis","sequence":"additional","affiliation":[{"name":"Department of Neuroscience , Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), , 16132 Genova , Italy"},{"name":"University of Genova, IRCCS AOU San Martino-IST , Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), , 16132 Genova , Italy"},{"name":"Department of Neurology, IRCCS Ospedale Policlinico San Martino , 16132 Genova , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0637-8971","authenticated-orcid":false,"given":"Maurizio","family":"D\u2019Antonio","sequence":"additional","affiliation":[{"name":"Biology of Myelin Unit , Division of Genetics and Cell Biology, , 20132 Milan , Italy"},{"name":"IRCCS Ospedale San Raffaele , Division of Genetics and Cell Biology, , 20132 Milan , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,7,31]]},"reference":[{"key":"2022121720475384000_ref1","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1038\/nrn1743","article-title":"Mechanisms of axon ensheathment and myelin growth","volume":"6","author":"Sherman","year":"2005","journal-title":"Nat. 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Neurol."},{"key":"2022121720475384000_ref10","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1093\/brain\/awh048","article-title":"Phenotypic clustering in MPZ mutations","volume":"127","author":"Shy","year":"2004","journal-title":"Brain"},{"key":"2022121720475384000_ref11","doi-asserted-by":"crossref","DOI":"10.1007\/s00415-019-09453-3","article-title":"Mutation update for myelin protein zero-related neuropathies and the increasing role of variants causing a late-onset phenotype","volume":"266","author":"Callegari","year":"2019","journal-title":"J. Neurol."},{"key":"2022121720475384000_ref12","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1084\/jem.20122005","article-title":"Resetting translational homeostasis restores myelination in Charcot-Marie-tooth disease type 1B mice","volume":"210","author":"D'Antonio","year":"2013","journal-title":"J. Exp. 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Neurol."},{"key":"2022121720475384000_ref16","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1038\/ng1581","article-title":"Gains of glycosylation comprise an unexpectedly large group of pathogenic mutations","volume":"37","author":"Vogt","year":"2005","journal-title":"Nat. Genet."},{"key":"2022121720475384000_ref17","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.gde.2007.04.008","article-title":"Gain-of-glycosylation mutations","volume":"17","author":"Vogt","year":"2007","journal-title":"Curr. Opin. Genet. 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