{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T17:08:49Z","timestamp":1792516129886,"version":"4.5.0"},"reference-count":35,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["STI2030\u2010Major Projects\u20102021ZD0202400"],"award-info":[{"award-number":["STI2030\u2010Major Projects\u20102021ZD0202400"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2024YFA1108000"],"award-info":[{"award-number":["2024YFA1108000"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82301774"],"award-info":[{"award-number":["82301774"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["movementdisorders.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Movement Disorders"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      SPG4, the most common hereditary spastic paraplegia caused by\u2009\n                      <jats:italic>SPAST<\/jats:italic>\n                      \u2009variants, exhibits extreme age\u2010at\u2010onset variability, indicative of uncharacterized genetic modifiers. The GJA1\n                      <jats:sup>R148Q<\/jats:sup>\n                      \u2009variant (linked to oculodentodigital dysplasia) may modulate SPG4 pathogenesis, yet its underlying molecular mechanism remains undefined.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      We investigated the molecular mechanism by which GJA1\n                      <jats:sup>R148Q<\/jats:sup>\n                      \u2009accelerates early SPG4 onset in a proband with dual\u2009\n                      <jats:italic>SPAST<\/jats:italic>\n                      \u2009and\u2009\n                      <jats:italic>GJA1<\/jats:italic>\n                      \u2009variants, and validated its function as a disease modifier for SPG4.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed comprehensive clinical phenotyping, segregation analysis, coimmunoprecipitation, ubiquitination analyses, CRISPR\u2010mediated correction in patient induced pluripotent stem cell2013derived organoids, and a targeted deubiquitinase screen.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The GJA1\n                      <jats:sup>R148Q<\/jats:sup>\n                      \u2009enhanced the physical interaction between SPASTIN and GJA1, accelerated the degradation of deubiquitinase valosin\u2010containing protein interacting protein 1 (VCPIP1), and thereby reduced SPASTIN levels. CRISPR\u2010based reversion of the R148Q restored SPASTIN levels and rescued microtubule\u2010severing function. Notably, maternal relatives carrying the\u2009\n                      <jats:italic>GJA1<\/jats:italic>\n                      <jats:sup>R148Q<\/jats:sup>\n                      \u2009allele alone exhibited no neurological abnormalities.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      The\u2009\n                      <jats:italic>GJA1<\/jats:italic>\n                      <jats:sup>R148Q<\/jats:sup>\n                      \u2009variant, although non\u2010neurological in isolation, acts as a disease modifier that precipitates SPG4 by exacerbating SPASTIN haploinsufficiency through destabilization of VCPIP1, positioning GJA1\u2010VCPIP1\u2010SPASTIN signaling as a potential therapeutic axis for SPG4 treatment. \u00a9 2026 International Parkinson and Movement Disorder Society.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mds.70248","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T21:13:32Z","timestamp":1773004412000},"page":"1863-1870","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A\n                    <scp>GJA1<\/scp>\n                    Variant Triggers Earlier\n                    <scp>SPG4<\/scp>\n                    Onset by Destabilizing Deubiquitinase\n                    <scp>VCPIP1<\/scp>\n                    to Lower\n                    <scp>SPASTIN<\/scp>\n                    Levels"],"prefix":"10.1002","volume":"41","author":[{"given":"Lingzi","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Rehabilitation Children's Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents' Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders  Chongqing China"},{"name":"Department of Neurology School of Basic Medical Sciences, Chongqing Medical University  Chongqing China"},{"name":"Department of Neurology The First Affiliated Hospital of Chongqing Medical University  Chongqing China"},{"name":"Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education) Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoran","family":"Chi","sequence":"additional","affiliation":[{"name":"Department of Neurology School of Basic Medical Sciences, Chongqing Medical University  Chongqing China"},{"name":"Department of Neurology The First Affiliated Hospital of Chongqing Medical University  Chongqing China"},{"name":"Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education) Chongqing Medical University  Chongqing 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