{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:20:41Z","timestamp":1785428441538,"version":"3.56.0"},"reference-count":41,"publisher":"Rockefeller University Press","issue":"4","license":[{"start":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T00:00:00Z","timestamp":1749513600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/rupress.org\/pages\/terms102024"}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,7,7]]},"abstract":"<jats:p>GJC2 encodes connexin 47 (Cx47), a gap junction protein expressed by oligodendrocytes that forms gap junction channels (GJCs) between adjacent oligodendrocytes (or astrocytes, via heterotypic Cx47\u2013Cx43 GJCs). Autosomal recessive mutations of GJC2 lead to at least three central nervous system phenotypes: Pelizaeus\u2013Merzbacher-like disease 1 (PMLD1), spastic paraparesis 44 (SPG44), and a minimal leukodystrophy. Here, we describe the clinical, functional, and molecular effects of two mutations in GJC2, p.G40S, and p.R244P, identified in two different families with GJC2-related disorders. Expressed exogenously, p.G40S forms GJC plaques like WT but does not functionally couple with WT nor with Cx43. p.R244P also fails to demonstrate functional coupling. Moreover, plaque formation is absent, concomitant with intracellular connexin accumulation. When the two mutants are co-expressed in a compound heterozygous state, plaques form, but no GJC coupling is detected in any configuration. MD simulations demonstrate that p.G40S modifies secondary structure of the pore-lining \u03b1-helix, disrupting supersecondary interactions with the N-terminal helix and predicting channel closure. p.R244P simulations are characterized by partial loss of the extracellular \u03b2-sheet domains and a marked reduction of electrostatic interactions between the connexin and lipid headgroups of the plasma membrane, suggesting pathways by which p.R244P mutation impairs GJC formation. This combination of in vitro assays and molecular simulations provides mechanistic insight into the pathogenesis of GJC2-related disease.<\/jats:p>","DOI":"10.1085\/jgp.202413617","type":"journal-article","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T02:20:31Z","timestamp":1746757231000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular dynamics simulation of\n                    <i>GJC2<\/i>\n                    mutants reveal pathogenic mechanisms of PMLD1 and SPG44"],"prefix":"10.1085","volume":"157","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7040-0382","authenticated-orcid":true,"given":"David","family":"Gong","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02mpq6x41","id-type":"ROR","asserted-by":"publisher"}],"name":"College of Medicine, University of Illinois Chicago 1 Department of Neurology and Rehabilitation, , Chicago, 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Pharmacy, Western University of Health Sciences 4 Department of Biotechnology and Pharmaceutical Sciences, , Pomona, CA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3456-0084","authenticated-orcid":true,"given":"Gabriel D.","family":"Dungan","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02mpq6x41","id-type":"ROR","asserted-by":"publisher"}],"name":"College of Medicine, University of Illinois Chicago 1 Department of Neurology and Rehabilitation, , Chicago, IL,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5737-5271","authenticated-orcid":true,"given":"Ayman W.","family":"El-Hattab","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00engpz63","id-type":"ROR","asserted-by":"publisher"}],"name":"College of Medicine, University of Sharjah 5 Department of Clinical Sciences, , Sharjah,","place":["United Arab 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