{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T14:24:20Z","timestamp":1787063060246,"version":"build-2736575974"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2021,4,1]],"date-time":"2021-04-01T00:00:00Z","timestamp":1617235200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000065","name":"NINDS","doi-asserted-by":"publisher","award":["U54NS065712"],"award-info":[{"award-number":["U54NS065712"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"NINDS","doi-asserted-by":"publisher","award":["R01NS105755"],"award-info":[{"award-number":["R01NS105755"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NCATS-ORD"},{"DOI":"10.13039\/100004952","name":"MDA","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004952","id-type":"DOI","asserted-by":"publisher"}]},{"name":"CMT-Association"},{"name":"Hereditary Neuropathy Foundation"},{"name":"The Genesis Project foundation"},{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Dr Miriam and Sheldon G. Adelson Medical Research Foundation"},{"name":"Hanna Hertz Professorial Chair for Multiple Sclerosis and Neuroscience"},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/T001712\/1"],"award-info":[{"award-number":["MR\/T001712\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002803","name":"Fondazione CARIPLO","doi-asserted-by":"publisher","award":["2019-1836"],"award-info":[{"award-number":["2019-1836"]}],"id":[{"id":"10.13039\/501100002803","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Italian Ministry of Health - Ricerca Corrente"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,5,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The CADM family of proteins consists of four neuronal specific adhesion molecules (CADM1, CADM2, CADM3 and CADM4) that mediate the direct contact and interaction between axons and glia. In the peripheral nerve, axon-Schwann cell interaction is essential for the structural organization of myelinated fibres and is primarily mediated by the binding of CADM3, expressed in axons, to CADM4, expressed by myelinating Schwann cells. We have identified\u2014by whole exome sequencing\u2014three unrelated families, including one de novo patient, with axonal Charcot-Marie-Tooth disease (CMT2) sharing the same private variant in CADM3, Tyr172Cys. This variant is absent in 230\u2009000 control chromosomes from gnomAD and predicted to be pathogenic. Most CADM3 patients share a similar phenotype consisting of autosomal dominant CMT2 with marked upper limb involvement. High resolution mass spectrometry analysis detected a newly created disulphide bond in the mutant CADM3 potentially modifying the native protein conformation. Our data support a retention of the mutant protein in the endoplasmic reticulum and reduced cell surface expression in vitro. Stochastic optical reconstruction microscopy imaging revealed decreased co-localization of the mutant with CADM4 at intercellular contact sites. Mice carrying the corresponding human mutation (Cadm3Y170C) showed reduced expression of the mutant protein in axons. Cadm3Y170C mice showed normal nerve conduction and myelin morphology, but exhibited abnormal axonal organization, including abnormal distribution of Kv1.2 channels and Caspr along myelinated axons. Our findings indicate the involvement of abnormal axon-glia interaction as a disease-causing mechanism in CMT patients with CADM3 mutations.<\/jats:p>","DOI":"10.1093\/brain\/awab019","type":"journal-article","created":{"date-parts":[[2021,1,27]],"date-time":"2021-01-27T23:41:12Z","timestamp":1611790872000},"page":"1197-1213","source":"Crossref","is-referenced-by-count":21,"title":["A\n                    <i>CADM3<\/i>\n                    variant causes Charcot-Marie-Tooth disease with marked upper limb involvement"],"prefix":"10.1093","volume":"144","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5669-7415","authenticated-orcid":false,"given":"Adriana P","family":"Rebelo","sequence":"first","affiliation":[{"name":"Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2208-5311","authenticated-orcid":false,"given":"Andrea","family":"Cortese","sequence":"additional","affiliation":[{"name":"MRC Centre for Neuromuscular Diseases, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK"},{"name":"Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Abraham","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yael","family":"Eshed-Eisenbach","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gal","family":"Shner","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Vainshtein","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Buglo","sequence":"additional","affiliation":[{"name":"Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir","family":"Camarena","sequence":"additional","affiliation":[{"name":"Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Gaidosh","sequence":"additional","affiliation":[{"name":"Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, USA"},{"name":"Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramin","family":"Shiekhattar","sequence":"additional","affiliation":[{"name":"Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, USA"},{"name":"Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Abreu","sequence":"additional","affiliation":[{"name":"Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Courel","sequence":"additional","affiliation":[{"name":"Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis K","family":"Burns","sequence":"additional","affiliation":[{"name":"Department of Pathology, UT Southwestern Medical Center, Dallas, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunhong","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chelsea","family":"Bacon","sequence":"additional","affiliation":[{"name":"Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shawna M E","family":"Feely","sequence":"additional","affiliation":[{"name":"Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Castro","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics, Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3325-0597","authenticated-orcid":false,"given":"Elior","family":"Peles","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary M","family":"Reilly","sequence":"additional","affiliation":[{"name":"MRC Centre for Neuromuscular Diseases, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael E","family":"Shy","sequence":"additional","affiliation":[{"name":"Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Zuchner","sequence":"additional","affiliation":[{"name":"Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,4,23]]},"reference":[{"key":"2021070719501027900_awab019-B1"},{"key":"2021070719501027900_awab019-B2","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1083\/jcb.200705132","article-title":"Nectin-like proteins mediate axon Schwann cell interactions along the internode and are essential for myelination","volume":"178","author":"Maurel","year":"2007","journal-title":"J Cell Biol"},{"key":"2021070719501027900_awab019-B3","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1038\/nn1915","article-title":"A central role for Necl4 (SynCAM4) in Schwann cell-axon interaction and myelination","volume":"10","author":"Spiegel","year":"2007","journal-title":"Nat Neurosci"},{"key":"2021070719501027900_awab019-B4","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1242\/jcs.01656","article-title":"Nectin-like molecule-1\/TSLL1\/SynCAM3: a neural tissue-specific immunoglobulin-like cell-cell adhesion molecule localizing at non-junctional contact sites of presynaptic nerve terminals, axons and glia cell processes","volume":"118","author":"Kakunaga","year":"2005","journal-title":"J Cell Sci"},{"key":"2021070719501027900_awab019-B5","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1523\/JNEUROSCI.2736-20.2020","article-title":"Differential Contribution of Cadm1-Cadm3 Cell Adhesion Molecules to Peripheral Myelinated Axons","volume":"41","author":"Sukhanov","year":"2021","journal-title":"J Neurosci"},{"key":"2021070719501027900_awab019-B6","doi-asserted-by":"crossref","first-page":"2247","DOI":"10.1002\/glia.23072","article-title":"Cadm3 (Necl-1) interferes with the activation of the PI3 kinase\/Akt signaling cascade and inhibits Schwann cell myelination in vitro","volume":"64","author":"Chen","year":"2016","journal-title":"Glia"},{"key":"2021070719501027900_awab019-B7","doi-asserted-by":"crossref","first-page":"10950","DOI":"10.1523\/JNEUROSCI.0571-13.2013","article-title":"Genetic deletion of Cadm4 results in myelin abnormalities resembling Charcot-Marie-Tooth neuropathy","volume":"33","author":"Golan","year":"2013","journal-title":"J Neurosci"},{"key":"2021070719501027900_awab019-B8","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.neuron.2018.11.032","article-title":"Axoglial Adhesion by Cadm4 Regulates CNS Myelination","volume":"101","author":"Elazar","year":"2019","journal-title":"Neuron"},{"key":"2021070719501027900_awab019-B9"},{"key":"2021070719501027900_awab019-B10","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1002\/acn3.543","article-title":"Myelin protein zero mutations and the unfolded protein response in Charcot Marie Tooth disease type 1B","volume":"5","author":"Bai","year":"2018","journal-title":"Ann Clin Transl Neurol"},{"key":"2021070719501027900_awab019-B11"},{"key":"2021070719501027900_awab019-B12","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.neuron.2010.02.004","article-title":"A glial signal consisting of gliomedin and NrCAM clusters axonal Na+ channels during the formation of nodes of Ranvier","volume":"65","author":"Feinberg","year":"2010","journal-title":"Neuron"},{"key":"2021070719501027900_awab019-B13","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/nmeth.3283","article-title":"Mapping native disulfide bonds at a proteome scale","volume":"12","author":"Lu","year":"2015","journal-title":"Nat Methods"},{"key":"2021070719501027900_awab019-B14","doi-asserted-by":"crossref","first-page":"8246","DOI":"10.1523\/JNEUROSCI.17-21-08246.1997","article-title":"Association and colocalization of the Kvbeta1 and Kvbeta2 beta-subunits with Kv1 alpha-subunits in mammalian brain K+ channel complexes","volume":"17","author":"Rhodes","year":"1997","journal-title":"J Neurosci"},{"key":"2021070719501027900_awab019-B15","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1093\/emboj\/16.5.978","article-title":"Identification of a novel contactin-associated transmembrane receptor with multiple domains implicated in protein-protein interactions","volume":"16","author":"Peles","year":"1997","journal-title":"EMBO J"},{"key":"2021070719501027900_awab019-B16","doi-asserted-by":"crossref","first-page":"2480","DOI":"10.1523\/JNEUROSCI.5225-09.2010","article-title":"Organization of myelinated axons by Caspr and Caspr2 requires the cytoskeletal adapter protein 4.1B","volume":"30","author":"Horresh","year":"2010","journal-title":"J Neurosci"},{"key":"2021070719501027900_awab019-B17","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1002\/humu.22836","article-title":"Innovative genomic collaboration using the GENESIS (GEM.app) platform","volume":"36","author":"Gonzalez","year":"2015","journal-title":"Human mutation"},{"key":"2021070719501027900_awab019-B18","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1101\/gr.3577405","article-title":"Distribution and intensity of constraint in mammalian genomic sequence","volume":"15","author":"Cooper","year":"2005","journal-title":"Genome Res"},{"key":"2021070719501027900_awab019-B19","doi-asserted-by":"crossref","first-page":"D886","DOI":"10.1093\/nar\/gky1016","article-title":"CADD: predicting the deleteriousness of variants throughout the human genome","volume":"47","author":"Rentzsch","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"2021070719501027900_awab019-B20","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1111\/j.1529-8027.2011.00350.x","article-title":"Reliability of the CMT neuropathy score (second version) in Charcot-Marie-Tooth disease","volume":"16","author":"Murphy","year":"2011","journal-title":"J Peripher Nerv Syst"},{"key":"2021070719501027900_awab019-B21","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"key":"2021070719501027900_awab019-B22","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.bbamem.2005.01.013","article-title":"Nectin-like molecule 1 is a protein 4.1N associated protein and recruits protein 4.1N from cytoplasm to the plasma membrane","volume":"1669","author":"Zhou","year":"2005","journal-title":"Biochim Biophys Acta"},{"key":"2021070719501027900_awab019-B23","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1038\/nmeth929","article-title":"Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM)","volume":"3","author":"Rust","year":"2006","journal-title":"Nat Methods"},{"key":"2021070719501027900_awab019-B24","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/S0896-6273(01)00294-X","article-title":"Axon-glia interactions and the domain organization of myelinated axons requires neurexin IV\/Caspr\/Paranodin","volume":"30","author":"Bhat","year":"2001","journal-title":"Neuron"},{"key":"2021070719501027900_awab019-B25","doi-asserted-by":"crossref","first-page":"e144","DOI":"10.1212\/NXG.0000000000000144","article-title":"CNTNAP1 mutations cause CNS hypomyelination and neuropathy with or without arthrogryposis","volume":"3","author":"Hengel","year":"2017","journal-title":"Neurol Genet"},{"key":"2021070719501027900_awab019-B26","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.ejmg.2017.02.006","article-title":"Identification of a novel CNTNAP1 mutation causing arthrogryposis multiplex congenita with cerebral and cerebellar atrophy","volume":"60","author":"Lakhani","year":"2017","journal-title":"Eur J Med Genet"},{"key":"2021070719501027900_awab019-B27","doi-asserted-by":"crossref","first-page":"2948","DOI":"10.1093\/brain\/awz248","article-title":"Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination","volume":"142","author":"Efthymiou","year":"2019","journal-title":"Brain"},{"key":"2021070719501027900_awab019-B28","doi-asserted-by":"crossref","first-page":"4794","DOI":"10.1038\/s41467-019-12789-z","article-title":"Two adhesive systems cooperatively regulate axon ensheathment and myelin growth in the CNS","volume":"10","author":"Djannatian","year":"2019","journal-title":"Nat Commun"}],"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awab019\/37306003\/awab019.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/brain\/article-pdf\/144\/4\/1197\/37903293\/awab019.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/brain\/article-pdf\/144\/4\/1197\/37903293\/awab019.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,7]],"date-time":"2021-07-07T17:28:25Z","timestamp":1625678905000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/article\/144\/4\/1197\/6247174"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,1]]},"references-count":28,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,4,23]]},"published-print":{"date-parts":[[2021,5,7]]}},"URL":"https:\/\/doi.org\/10.1093\/brain\/awab019","relation":{},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,4,1]]},"published":{"date-parts":[[2021,4,1]]}}}