{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T02:34:37Z","timestamp":1777343677866,"version":"3.51.4"},"reference-count":30,"publisher":"BMJ","issue":"4","funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82271436"],"award-info":[{"award-number":["82271436"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Qingdao Science and Technology Benefit People Demonstration Guide Special Project","award":["22-8-7-smjk-1-nsh"],"award-info":[{"award-number":["22-8-7-smjk-1-nsh"]}]},{"DOI":"10.13039\/501100007129","name":"Shandong Provincial Natural Science Foundation","doi-asserted-by":"crossref","award":["ZR2022MH190"],"award-info":[{"award-number":["ZR2022MH190"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2023,10,14]]},"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Mutations in the tropomyosin receptor kinase fused (<jats:italic>TFG<\/jats:italic>) gene are associated with various neurological disorders, including autosomal recessive hereditary spastic paraplegia (HSP), autosomal dominant hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) and autosomal dominant type of Charcot-Marie-Tooth disease type 2.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Whole genome sequencing and whole-exome sequencing were used, followed by Sanger sequencing for validation. Haplotype analysis was performed to confirm the inheritance mode of the novel <jats:italic>TFG<\/jats:italic> mutation in a large Chinese family with HSP. Additionally, another family diagnosed with HMSN-P and carrying the reported <jats:italic>TFG<\/jats:italic> mutation was studied. Clinical data and muscle pathology comparisons were drawn between patients with HSP and patients with HMSN-P. Furthermore, functional studies using skin fibroblasts derived from patients with HSP and patients with HMSN-P were conducted to investigate the pathomechanisms of <jats:italic>TFG<\/jats:italic> mutations.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>A novel heterozygous <jats:italic>TFG<\/jats:italic> variant (NM_006070.6: c.125G&gt;A (p.R42Q)) was identified and caused pure HSP. We further confirmed that the well-documented recessively inherited spastic paraplegia, caused by homozygous <jats:italic>TFG<\/jats:italic> mutations, exists in a dominantly inherited form. Although the clinical features and muscle pathology between patients with HSP and patients with HMSN-P were distinct, skin fibroblasts derived from both patient groups exhibited reduced levels of autophagy-related proteins and the presence of TFG-positive puncta.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Our findings suggest that autophagy impairment may serve as a common pathomechanism among different clinical phenotypes caused by <jats:italic>TFG<\/jats:italic> mutations. Consequently, targeting autophagy may facilitate the development of a uniform treatment for TFG-related neurological disorders.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg-2023-109485","type":"journal-article","created":{"date-parts":[[2023,10,27]],"date-time":"2023-10-27T13:25:37Z","timestamp":1698413137000},"page":"325-331","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Novel <i>TFG<\/i> mutation causes autosomal-dominant spastic paraplegia and defects in autophagy"],"prefix":"10.1136","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4058-2810","authenticated-orcid":false,"given":"Ling","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Neurology and Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, Jinan, Shandong 250012, 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