title: TFG-Related Neurologic Disorders: New Insights Into Relationships Between Endoplasmic Reticulum and Neurodegeneration.
abstract: The tropomyosin-receptor kinase fused gene(TFG), which is located on chromosome 3q12.2, was originally identified as a fusion partner that results in the formation of oncogenic products associated with multiple cancers. TFG protein interacts directly with Sec16, the scaffolding protein for coat protein II-coated vesicles that regulate endoplasmic reticulum (ER)-to-Golgi transport at ER exit sites. In 2012, a heterozygous mutation of TFG was identified as the causative gene for autosomal-dominant hereditary motor and sensory neuropathy with proximal dominant involvement. In 2013, a homozygous mutation of TFG was reported in a family with early onset spastic paraplegia, optic atrophy, and neuropathy. Another novel mutation in TFG was discovered in 2014 as a cause of dominant axonal Charcot-Marie-Tooth disease type 2. These findings suggest that mutations of TFG cause ER dysfunction and neurodegeneration in this disease spectrum, which is tightly associated with ER function. Here, we review the clinical phenotypes of these diseases and present recent insights that suggest causal roles of ER dysfunction in TFG-related neurologic disorders. Although the precise pathogenetic mechanisms underlying these TFG mutations remain to be elucidated, experimental manipulations suggest that the dysregulations of ER homeostasis that occur due to mutations in TFG lead to neurodegeneration.
authors.affiliation: From the Department of Neurology, School of Medicine, Keio University, Shinjuku-Ku, Tokyo, Japan (TY, DI, NS) and Department of Medicine, Washington University School of Medicine, St Louis, Missouri (TY). takuyagi@2006.jukuin.keio.ac.jp.
authors.forename: Takuya
authors.initials: T
authors.lastname: Yagi
authors.affiliation: From the Department of Neurology, School of Medicine, Keio University, Shinjuku-Ku, Tokyo, Japan (TY, DI, NS) and Department of Medicine, Washington University School of Medicine, St Louis, Missouri (TY).
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ito
authors.affiliation: From the Department of Neurology, School of Medicine, Keio University, Shinjuku-Ku, Tokyo, Japan (TY, DI, NS) and Department of Medicine, Washington University School of Medicine, St Louis, Missouri (TY).
authors.forename: Norihiro
authors.initials: N
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D009154:Mutation / Q000235:genetics; D009422:Nervous System Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D033921:Vesicular Transport Proteins
chemical_list: D011506:Proteins; C096163:TFG protein, human; D033921:Vesicular Transport Proteins
keywords: Charcot-Marie-Tooth disease; Endoplasmic reticulum; Neurodegeneration; Spastic paraplegia; Tropomyosin-receptor kinase fused gene (TFG).