{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T02:29:59Z","timestamp":1780108199326,"version":"3.54.0"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2018,9,19]],"date-time":"2018-09-19T00:00:00Z","timestamp":1537315200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003653","name":"Korea National Institute of Health","doi-asserted-by":"publisher","award":["R01 NS55256"],"award-info":[{"award-number":["R01 NS55256"]}],"id":[{"id":"10.13039\/501100003653","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003653","name":"Korea National Institute of Health","doi-asserted-by":"publisher","award":["R56NS096104"],"award-info":[{"award-number":["R56NS096104"]}],"id":[{"id":"10.13039\/501100003653","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100002721","name":"Charcot-Marie-Tooth Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002721","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/M008606\/1"],"award-info":[{"award-number":["MR\/M008606\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000406","name":"Motor Neurone Disease Association","doi-asserted-by":"publisher","award":["MR\/M008606\/1"],"award-info":[{"award-number":["MR\/M008606\/1"]}],"id":[{"id":"10.13039\/501100000406","id-type":"DOI","asserted-by":"publisher"}]},{"name":"UCLH NIHR Biomedical Research Centre"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Protein zero (P0) is the major structural protein in peripheral myelin, and mutations in the Myelin Protein Zero (Mpz) gene produce wide-ranging hereditary neuropathy phenotypes. To gain insight in the mechanisms underlying a particularly severe form, congenital hypomyelination (CH), we targeted mouse Mpz to encode P0Q215X, a nonsense mutation associated with the disease, that we show escapes nonsense mediated decay and is expressed in CH patient nerves. The knock-in mice express low levels of the resulting truncated protein, producing a milder phenotype when compared to patients, allowing to dissect the subtle pathogenic mechanisms occurring in otherwise very compromised peripheral myelin. We find that P0Q215X does not elicit an unfolded protein response, which is a key mechanism for other pathogenic MPZ mutations, but is instead in part aberrantly trafficked to non-myelin plasma membranes and induces defects in radial sorting of axons by Schwann cells. We show that the loss of the C-terminal Tyr-Ala-Met-Leu motif is responsible for P0 mislocalization, as its addition is able to restore correct P0Q215X trafficking in vitro. Lastly, we show that P0Q215X acts through dose-dependent gain of abnormal function, as wild-type P0 is unable to rescue the hypomyelination phenotype. Collectively, these data indicate that alterations at the premyelinating stage, linked to altered targeting of P0, may be responsible for CH, and that different types of gain of abnormal function produce the diverse neuropathy phenotypes associated with MPZ, supporting future allele-specific therapeutic silencing strategies.<\/jats:p>","DOI":"10.1093\/hmg\/ddy336","type":"journal-article","created":{"date-parts":[[2018,9,18]],"date-time":"2018-09-18T15:15:38Z","timestamp":1537283738000},"page":"124-132","source":"Crossref","is-referenced-by-count":22,"title":["A nonsense mutation in myelin protein zero causes congenital hypomyelination neuropathy through altered P0 membrane targeting and gain of abnormal function"],"prefix":"10.1093","volume":"28","author":[{"given":"Pietro","family":"Fratta","sequence":"first","affiliation":[{"name":"UCL Institute of Neurology, Queen Square, London WC1N, UK"},{"name":"IRCCS San Raffaele Scientific Institute, DIBIT, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Ornaghi","sequence":"additional","affiliation":[{"name":"IRCCS San Raffaele Scientific Institute, DIBIT, Milan, Italy"},{"name":"SR-TIGET, Milan, Italy"},{"name":"Departments of Neurology and Biochemistry, Jacobs School of Medicine and Biomedical Sciences, Hunter James Kelly Research Institute, State University of New York at Buffalo, Buffalo, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Dati","sequence":"additional","affiliation":[{"name":"IRCCS San Raffaele Scientific Institute, DIBIT, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Desir\u00e9e","family":"Zambroni","sequence":"additional","affiliation":[{"name":"IRCCS San Raffaele Scientific Institute, DIBIT, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Saveri","sequence":"additional","affiliation":[{"name":"IRCCS San Raffaele Scientific Institute, DIBIT, Milan, Italy"},{"name":"Unit of Rare Neurodegenerative and Neurometabolic Diseases, Department of Clinical Neurosciences, C. Besta Neurological Institute IRCCS Foundation, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Belin","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Experimental Therapeutics, Albany Medical College Department of Neuroscience and Experimental Therapeutics, Albany, NY, USA"},{"name":"Departments of Neurology and Biochemistry, Jacobs School of Medicine and Biomedical Sciences, Hunter James Kelly Research Institute, State University of New York at Buffalo, Buffalo, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"D\u2019Adamo","sequence":"additional","affiliation":[{"name":"IRCCS San Raffaele Scientific Institute, DIBIT, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Shy","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelo","family":"Quattrini","sequence":"additional","affiliation":[{"name":"IRCCS San Raffaele Scientific Institute, DIBIT, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Laura Feltri","sequence":"additional","affiliation":[{"name":"IRCCS San Raffaele Scientific Institute, DIBIT, Milan, Italy"},{"name":"Departments of Neurology and Biochemistry, Jacobs School of Medicine and Biomedical Sciences, Hunter James Kelly Research Institute, State University of New York at Buffalo, Buffalo, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence","family":"Wrabetz","sequence":"additional","affiliation":[{"name":"IRCCS San Raffaele Scientific Institute, DIBIT, Milan, Italy"},{"name":"Departments of Neurology and Biochemistry, Jacobs School of Medicine and Biomedical Sciences, Hunter James Kelly Research Institute, State University of New York at Buffalo, Buffalo, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,9,19]]},"reference":[{"key":"2019102302292248700_ref1","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1002\/jnr.490350107","article-title":"Production and characterization of monoclonal antibodies to the extracellular domain of P0","volume":"35","author":"Archelos","year":"1993","journal-title":"J. Neurosci. Res."},{"key":"2019102302292248700_ref2","doi-asserted-by":"crossref","first-page":"2664","DOI":"10.1093\/brain\/awr184","article-title":"Genetic spectrum of hereditary neuropathies with onset in the first year of life","volume":"134","author":"Baets","year":"2011","journal-title":"Brain"},{"key":"2019102302292248700_ref3","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/0896-6273(90)90057-M","article-title":"Protein zero of peripheral nerve myelin: biosynthesis, membrane insertion, and evidence for homotypic interaction","volume":"4","author":"D'Urso","year":"1990","journal-title":"Neuron"},{"key":"2019102302292248700_ref4","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1046\/j.1460-9568.1999.00568.x","article-title":"A novel P0 glycoprotein transgene activates expression of lacZ in myelin-forming Schwann cells","volume":"11","author":"Feltri","year":"1999","journal-title":"Eur. J. Neurosci."},{"key":"2019102302292248700_ref5","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1038\/344871a0","article-title":"Role of myelin P0 protein as a homophilic adhesion molecule","volume":"344","author":"Filbin","year":"1990","journal-title":"Nature"},{"key":"2019102302292248700_ref6","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1093\/hmg\/ddr081","article-title":"P0S63del impedes the arrival of wild-type P0 glycoprotein to myelin in CMT1B mice","volume":"20","author":"Fratta","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"2019102302292248700_ref7","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/0092-8674(92)90591-Y","article-title":"Mouse P0 gene disruption leads to hypomyelination, abnormal expression of recognition molecules, and degeneration of myelin and axons","volume":"71","author":"Giese","year":"1992","journal-title":"Cell"},{"key":"2019102302292248700_ref8","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1111\/j.1471-4159.1973.tb00089.x","article-title":"Protein composition of myelin of the peripheral nervous system","volume":"20","author":"Greenfield","year":"1973","journal-title":"J. Neurochem."},{"key":"2019102302292248700_ref9","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/0378-1119(89)90358-2","article-title":"Site-directed mutagenesis by overlap extension using the polymerase chain reaction","volume":"77","author":"Ho","year":"1989","journal-title":"Gene"},{"key":"2019102302292248700_ref10","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1002\/ana.10404","article-title":"Congenital hypomyelinating neuropathy, central dysmyelination, and Waardenburg-Hirschsprung disease: phenotypes linked by SOX10 mutation","volume":"52","author":"Inoue","year":"2002","journal-title":"Ann. Neurol."},{"key":"2019102302292248700_ref11","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/ng1322","article-title":"Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations","volume":"36","author":"Inoue","year":"2004","journal-title":"Nat. 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Cell. Biol."},{"key":"2019102302292248700_ref23","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/S0896-6273(00)80177-4","article-title":"Clinical phenotypes of different MPZ (P0) mutations may include Charcot-Marie-Tooth type 1B, Dejerine-Sottas, and congenital hypomyelination","volume":"17","author":"Warner","year":"1996","journal-title":"Neuron"},{"key":"2019102302292248700_ref24","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1083\/jcb.126.4.1089","article-title":"The cytoplasmic domain of the myelin P0 protein influences the adhesive interactions of its extracellular domain","volume":"126","author":"Wong","year":"1994","journal-title":"J. Cell. Biol."},{"key":"2019102302292248700_ref25","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1083\/jcb.134.6.1531","article-title":"Dominant-negative effect on adhesion by myelinPo protein truncated in its cytoplasmic domain","volume":"134","author":"Wong","year":"1996","journal-title":"J. Cell. Biol."},{"key":"2019102302292248700_ref26","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1083\/jcb.148.5.1021","article-title":"P(0) glycoprotein overexpression causes congenital hypomyelination of peripheral nerves","volume":"148","author":"Wrabetz","year":"2000","journal-title":"J. Cell. Biol."},{"key":"2019102302292248700_ref27","doi-asserted-by":"crossref","first-page":"2358","DOI":"10.1523\/JNEUROSCI.3819-05.2006","article-title":"Different intracellular pathomechanisms produce diverse myelin protein zero neuropathies in transgenic mice","volume":"26","author":"Wrabetz","year":"2006","journal-title":"J. Neurosci."},{"key":"2019102302292248700_ref28","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1083\/jcb.200107114","article-title":"Mutations in the cytoplasmic domain of P0 reveal a role for PKC-mediated phosphorylation in adhesion and myelination","volume":"155","author":"Xu","year":"2001","journal-title":"J. Cell Biol."},{"key":"2019102302292248700_ref29","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1083\/jcb.148.5.1009","article-title":"Schwann cell myelination requires timely and precise targeting of P0 protein","volume":"148","author":"Yin","year":"2000","journal-title":"J. Cell Biol."},{"key":"2019102302292248700_ref30","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1172\/JCI96499","article-title":"PMP22 antisense oligonucleotides reverse Charcot-Marie-Tooth disease type 1A features in rodent models","volume":"128","author":"Zhao","year":"2018","journal-title":"J. Clin. Invest."}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/28\/1\/124\/30262160\/ddy336.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/28\/1\/124\/30262160\/ddy336.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,10,23]],"date-time":"2019-10-23T02:30:00Z","timestamp":1571797800000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/28\/1\/124\/5103512"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,9,19]]},"references-count":30,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,9,19]]},"published-print":{"date-parts":[[2019,1,1]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddy336","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/352112","asserted-by":"object"}]},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,1,1]]},"published":{"date-parts":[[2018,9,19]]}}}