{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T13:49:17Z","timestamp":1791553757042,"version":"4.3.4"},"reference-count":41,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T00:00:00Z","timestamp":1791504000000},"content-version":"vor","delay-in-days":281,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"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\/501100004000","name":"Guangzhou Science and Technology Program key projects","doi-asserted-by":"publisher","award":["2024B03J1257"],"award-info":[{"award-number":["2024B03J1257"]}],"id":[{"id":"10.13039\/501100004000","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Human Mutation"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>\n                      Charcot\u2013Marie\u2013Tooth disease X\u2010linked Type 1 (CMTX1), caused by\n                      <jats:italic>GJB1<\/jats:italic>\n                      mutations, presents diagnostic challenges due to phenotypic heterogeneity and novel variants. This study reviews clinical data from 2021\u20132024 and investigates the mechanisms of two novel\n                      <jats:italic>GJB1<\/jats:italic>\n                      variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We retrospectively analyzed eight male patients, evaluating clinical signs, electrophysiology, and sural nerve biopsies. Pathogenicity of novel variants was assessed via bioinformatics, ChimeraX molecular modeling, and HeLa cell models focusing on protein localization and channel function (scratch\u2010loading\/DAPI assays).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Patients showed typical distal muscle atrophy and intermediate conduction velocities; three exhibited rare CNS white matter abnormalities. Two novel variants were identified: c.130dupT and c.124A\u2009&gt;\u2009G. c.130dupT led to a complete \u201closs of expression\u201d of the full\u2010length Cx32 protein. c.124A\u2009&gt;\u2009G resulted in significant cytoplasmic protein retention (\n                      <jats:italic>p<\/jats:italic>\n                      &lt; 0.05). Molecular modeling revealed a physical constriction (1.229\u2009\u00c5) in the channel bottleneck and an increased electrostatic barrier. Functional assays confirmed significant impairment in both gap junction and hemichannel activity (\n                      <jats:italic>p<\/jats:italic>\n                      &lt; 0.01).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      This study identifies two previously unreported\n                      <jats:italic>GJB1<\/jats:italic>\n                      variants and elucidates their distinct pathogenic mechanisms: c.130dupT acts through loss of expression, whereas c.124A\u2009&gt;\u2009G causes functional defect via structural channel constriction. These findings expand the genetic spectrum of CMTX1 and provide a basis for precise molecular diagnosis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1155\/humu\/7388252","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T12:56:02Z","timestamp":1791550562000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pathogenic Mechanisms of Two Novel Variants in the GJB1 Gene"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2057-1486","authenticated-orcid":false,"given":"Fenliang","family":"Xiao","sequence":"first","affiliation":[{"name":"Department of Neurology Nanfang Hospital Southern Medical University  Guangzhou Guangdong China  fimmu.com"},{"name":"Key Laboratory of Mental Health of the Ministry of Education Southern Medical University  Guangzhou Guangdong China  fimmu.com"},{"name":"Guangdong-Hong Kong-Macao 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