{"id":82,"date":"2023-10-27T16:00:19","date_gmt":"2023-10-27T16:00:19","guid":{"rendered":"http:\/\/sebgc.es\/blog\/?guid=ceaf72c88eebac2c22c3633e7ae3abcc"},"modified":"2023-10-27T16:00:19","modified_gmt":"2023-10-27T16:00:19","slug":"novel-tfg-mutation-causes-autosomal-dominant-spastic-paraplegia-and-defects-in-autophagy","status":"publish","type":"post","link":"https:\/\/sebigec.es\/blog\/index.php\/2023\/10\/27\/novel-tfg-mutation-causes-autosomal-dominant-spastic-paraplegia-and-defects-in-autophagy\/","title":{"rendered":"Novel TFG mutation causes autosomal-dominant spastic paraplegia and defects in autophagy"},"content":{"rendered":"<sec><st>Background<\/st><p>Mutations in the tropomyosin receptor kinase fused (<I>TFG<\/I>) 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.<\/p><\/sec><sec><st>Methods<\/st><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 <I>TFG<\/I> mutation in a large Chinese family with HSP. Additionally, another family diagnosed with HMSN-P and carrying the reported <I>TFG<\/I> 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 <I>TFG<\/I> mutations.<\/p><\/sec><sec><st>Results<\/st><p>A novel heterozygous <I>TFG<\/I> 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 <I>TFG<\/I> 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.<\/p><\/sec><sec><st>Conclusions<\/st><p>Our findings suggest that autophagy impairment may serve as a common pathomechanism among different clinical phenotypes caused by <I>TFG<\/I> mutations. Consequently, targeting autophagy may facilitate the development of a uniform treatment for TFG-related neurological disorders.<\/p><\/sec>","protected":false},"excerpt":{"rendered":"<p>BackgroundMutations in the tropomyosin receptor kinase fused (TFG) gene are associated with various neurological disorders, including autosomal recessive hereditary spastic paraplegia (HSP), autosomal dominant hereditary motor and sensory neuropathy wi&#8230;<\/p>\n","protected":false},"author":8,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[6,8],"tags":[],"class_list":["post-82","post","type-post","status-publish","format-standard","hentry","category-articulos","category-jmg-first"],"_links":{"self":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts\/82","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/users\/8"}],"replies":[{"embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/comments?post=82"}],"version-history":[{"count":1,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts\/82\/revisions"}],"predecessor-version":[{"id":83,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts\/82\/revisions\/83"}],"wp:attachment":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/media?parent=82"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/categories?post=82"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/tags?post=82"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}