{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T02:15:19Z","timestamp":1792721719952,"version":"4.5.0"},"reference-count":21,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2022,6,9]],"date-time":"2022-06-09T00:00:00Z","timestamp":1654732800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81870889"],"award-info":[{"award-number":["81870889"]}],"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":["82071258"],"award-info":[{"award-number":["82071258"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Spastic paraplegia\u201012 (SPG12) is a subtype of hereditary spastic paraplegia caused by Reticulon\u20102 (<jats:italic>RTN2<\/jats:italic>) mutations. We described the clinical and genetic features of three SPG12 patients, functionally explored the potential pathogenic mechanism of <jats:italic>RTN2<\/jats:italic> mutations, and reviewed <jats:italic>RTN2<\/jats:italic>\u2010related cases worldwide.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The three patients were 31, 36, and 50\u2009years old, respectively, with chronic progressive lower limb spasticity and walking difficulty. Physical examination showed elevated muscle tone, hyperreflexia and Babinski signs in the lower limbs. Patients 1 and 3 additionally had visual, urinary, and\/or coordination dysfunctions. Patient 2 also had epileptic seizures. <jats:italic>RTN2<\/jats:italic> mutations were identified by whole\u2010exome sequencing, followed by Sanger sequencing, segregation analysis, and phenotypic reevaluation. Functional examination of identified mutations was further explored.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Three variants in <jats:italic>RTN2<\/jats:italic> were identified in Patient 1 (c.103C&gt;T, p.R35X), Patient 2 (c.230G&gt;A, p.G77D), and Patient 3 (c.337C&gt;A, p.P113T) with SPG, respectively. Western blotting revealed the p.R35X with smaller molecular weight than WT and other two missense mutants. Immunostaining showed the wild type colocalized with endoplasmic reticulum (ER) in\u00a0vitro. p.R35X mutant diffusely distributes in the cytoplasm, losing colocalization with ER. p.G77D and p.P113T co\u2010localized with ER, which was abnormally aggregated in clumps.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>In this study, we identified three cases with complicated SPG12 due to three novel <jats:italic>RTN2<\/jats:italic> mutations, respectively, presenting various phenotypes: classic SPG symptoms with (1) visual abnormalities and sphincter disturbances or (2) seizures. The phenotypic heterogeneity might arise from the abnormal subcellular localization of mutant Reticulon\u20102 and improper ER morphogenesis, revealing the <jats:italic>RTN2<\/jats:italic>\u2010related spectrum is still expanding.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51605","type":"journal-article","created":{"date-parts":[[2022,6,10]],"date-time":"2022-06-10T05:24:06Z","timestamp":1654838646000},"page":"1108-1115","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["New phenotype of <scp><i>RTN2<\/i><\/scp>\u2010related spectrum: Complicated form of spastic paraplegia\u201012"],"prefix":"10.1002","volume":"9","author":[{"given":"Wotu","family":"Tian","sequence":"first","affiliation":[{"name":"Department of Neurology Shanghai Jiao Tong University Affiliated Sixth People's Hospital  Shanghai 200233 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Neurology Shanghai Jiao Tong University Affiliated Sixth People's Hospital  Shanghai 200233 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1742-9877","authenticated-orcid":false,"given":"Li","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Neurology Shanghai Jiao Tong University Affiliated Sixth People's Hospital  Shanghai 200233 China"},{"name":"School of Medicine Anhui University of Science and Technology  Huainan 232001 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