{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T05:07:42Z","timestamp":1773032862585,"version":"3.50.1"},"reference-count":73,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T00:00:00Z","timestamp":1769040000000},"content-version":"vor","delay-in-days":21,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82271893"],"award-info":[{"award-number":["82271893"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82302090"],"award-info":[{"award-number":["82302090"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Charcot\u2013Marie\u2013Tooth disease (CMT), an inherited neuropathy characterized by progressive distal muscle weakness and atrophy, is associated with axonal impairment. Although mutations in the TRK\u2010fused gene (\n                    <jats:italic>TFG<\/jats:italic>\n                    ) have been linked to both CMT and hereditary spastic paraplegia, their pathogenic mechanisms remain poorly understood. Previously, we have demonstrated that the TFG p.G269V mutation causes progressive muscle weakness in patients, impairs neurite outgrowth in primary cultured mouse neurons, and induces neuronal apoptosis in zebrafish, suggesting a conserved role in neurodevelopment. To investigate its effects in human models, we established induced pluripotent stem cells (iPSCs) from patients carrying the mutation and generated homologous correction lines using CRISPR\/Cas9 editing. Both cell lines differentiated into motor neurons (MNs). Although neuronal differentiation and the expression of maturation markers were comparable, the patient\u2010derived MNs exhibited significant axonal shortening and TFG\u2010associated insoluble material. Electrophysiological assessment revealed functional deficits, including reduced spontaneous and evoked action potential frequencies and elevated rheobase. Transcriptomic analysis revealed dysregulation of Wnt signaling, and pharmacological inhibition of this pathway further exacerbated the loss of neuronal excitability. Our findings indicate that the TFG p.G269V mutation autonomously disrupts MN morphology and function and that these defects can be reversed using genetic correction. Moreover, dysregulated Wnt signaling may contribute to the pathophysiology of TFG\u2010associated neuropathy.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70359-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70359","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T05:50:35Z","timestamp":1769147435000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>TFG<\/scp>\n                    p.\n                    <scp>G269V<\/scp>\n                    Mutation Disrupts Motor Neuron Function in\n                    <scp>iPSC<\/scp>\n                    \u2010Derived Models via Wnt Signaling Dysregulation"],"prefix":"10.1111","volume":"170","author":[{"given":"Zhiqiang","family":"Mu","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Shaanxi Provincial Key Laboratory of Clinical Genetics, School of Basic Medicine Fourth Military Medical University  Xi'an Shaanxi People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jielin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Shaanxi Provincial Key Laboratory of Clinical Genetics, School of Basic Medicine Fourth Military Medical University  Xi'an Shaanxi People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tian","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Shaanxi Provincial Key Laboratory of Clinical Genetics, School of Basic Medicine Fourth Military Medical University  Xi'an Shaanxi People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4433-127X","authenticated-orcid":false,"given":"Kun","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology and Embryology and K.K. Leung Brain Research Centre, School of Basic Medicine Fourth Military Medical University  Xi'an Shaanxi People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinyu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Shaanxi Provincial Key Laboratory of Clinical Genetics, School of Basic Medicine Fourth Military Medical University  Xi'an Shaanxi People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiurong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Shaanxi Provincial Key Laboratory of Clinical Genetics, School of Basic Medicine Fourth Military Medical University  Xi'an Shaanxi People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiahui","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Shaanxi Provincial Key Laboratory of Clinical Genetics, School of Basic Medicine Fourth Military Medical University  Xi'an Shaanxi People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuanbo","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Shaanxi Provincial Key Laboratory of Clinical Genetics, School of Basic Medicine Fourth Military Medical University  Xi'an Shaanxi People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology and Embryology and K.K. Leung Brain Research Centre, School of Basic Medicine Fourth Military Medical University  Xi'an Shaanxi People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuanming","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Shaanxi Provincial Key Laboratory of Clinical Genetics, School of Basic Medicine Fourth Military Medical University  Xi'an Shaanxi People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fangfang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medicine Fourth Military Medical University  Xi'an People's Republic of 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