{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T05:50:33Z","timestamp":1787637033794,"version":"build-2736575974"},"reference-count":34,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T00:00:00Z","timestamp":1692662400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Peripheral Nervous Sys"],"published-print":{"date-parts":[[2023,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Charcot\u2013Marie\u2013Tooth disease type 1X is caused by mutations in <jats:italic>GJB1<\/jats:italic>, which is the second most common gene associated with inherited peripheral neuropathy. The <jats:italic>GJB1<\/jats:italic> gene encodes connexin 32 (CX32), a gap junction protein expressed in myelinating glial cells. The gene is X\u2010linked, and the mutations cause a loss of function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aims<\/jats:title><jats:p>A large number of disease\u2010associated variants have been identified, and many result in mistrafficking and mislocalization of the protein. An existing knockout mouse lacking <jats:italic>Gjb1<\/jats:italic> expression provides a valid animal model of CMT1X, but the complete lack of protein may not fully recapitulate the disease mechanisms caused by aberrant CX32 proteins. To better represent the spectrum of human CMT1X\u2010associated mutations, we have generated a new <jats:italic>Gjb1<\/jats:italic> knockin mouse model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>CRISPR\/Cas9 genome editing was used to produce mice carrying the R15Q mutation in <jats:italic>Gjb1<\/jats:italic>. In addition, we identified a second allele with an early frame shift mutation in codon 7 (del2). Mice were analyzed using clinically relevant molecular, histological, neurophysiological, and behavioral assays.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Both alleles produce protein detectable by immunofluorescence in Schwann cells, with some protein properly localizing to nodes of Ranvier. However, both alleles also result in peripheral neuropathy with thinly myelinated and demyelinated axons, as well as degenerating and regenerating axons, predominantly in distal motor nerves. Nerve conduction velocities were only mildly reduced at later ages and compound muscle action potential amplitudes were not reduced. Levels of neurofilament light chain in plasma were elevated in both alleles. The del2 mice have an onset at ~3\u2009months of age, whereas the R15Q mice had a later onset at 5\u20136\u2009months of age, suggesting a milder loss of function. Both alleles performed comparably to wild type littermates in accelerating rotarod and grip strength tests of neuromuscular performance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>We have generated and characterized two new mouse models of CMT1X that will be useful for future mechanistic and preclinical studies.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jns.12588","type":"journal-article","created":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T05:46:05Z","timestamp":1691473565000},"page":"317-328","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Two new mouse models of <scp><i>Gjb1<\/i><\/scp>\u2010associated <scp>Charcot\u2013Marie\u2013Tooth<\/scp> disease type <scp>1X<\/scp>"],"prefix":"10.1111","volume":"28","author":[{"given":"A. L. 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P.","family":"Bogdanik","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory  Bar Harbor Maine USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9229-3407","authenticated-orcid":false,"given":"Robert W.","family":"Burgess","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory  Bar Harbor Maine USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,8,22]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.106"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2014-308826"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1529-8027.2012.00424.x"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41434-021-00250-0"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddz199"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1522202113"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000095960.48964.25"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e3181efa658"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.8266101"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000256709.08271.4d"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.15-12-08281.1995"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2019.00069"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.10255"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1006\/nbdi.2002.0545"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx064"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.18.9565"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2022.114277"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.17-12-04545.1997"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-1136(199809)24:1<8::AID-GLIA2>3.0.CO;2-3"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2006.05.001"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.22279"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0325-09.2009"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2020.00690"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(00)03327-8"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1999.tb08598.x"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2018.00227"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-60761-058-8_20"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.03.009"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1809430115"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.16144"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/jns.12477"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00335-019-09798-0"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2019.146572"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000004932"}],"container-title":["Journal of the Peripheral Nervous System"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jns.12588","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T13:21:36Z","timestamp":1698844896000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jns.12588"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,22]]},"references-count":34,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2023,9]]}},"alternative-id":["10.1111\/jns.12588"],"URL":"https:\/\/doi.org\/10.1111\/jns.12588","archive":["Portico"],"relation":{},"ISSN":["1085-9489","1529-8027"],"issn-type":[{"value":"1085-9489","type":"print"},{"value":"1529-8027","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,22]]},"assertion":[{"value":"2023-01-31","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-08-04","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-08-22","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}