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TFG-Related Neurologic Disorders: New Insights Into Relationships Between Endoplasmic Reticulum and Neurodegeneration
Takuya Yagi1, Daisuke Ito2, Norihiro Suzuki2
1From 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.
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.
Insights
Mutations in the tropomyosin-receptor kinase fused gene (TFG) disrupt endoplasmic reticulum (ER) function, leading to neurodegenerative disorders. This review explores TFG-related diseases and the role of ER dysfunction in their pathogenesis.
Area of Science:
- Genetics and Molecular Biology
- Neuroscience
- Cell Biology
Background:
- The tropomyosin-receptor kinase fused gene (TFG) is implicated in oncogenesis and cellular transport.
- TFG protein interacts with Sec16, crucial for endoplasmic reticulum (ER) to Golgi transport.
- Mutations in TFG have been linked to various inherited neurological disorders.
Purpose of the Study:
- To review the clinical spectrum of TFG-related neurological diseases.
- To present current insights into the role of ER dysfunction in these disorders.
- To highlight the connection between TFG mutations, ER homeostasis, and neurodegeneration.
Main Methods:
- Literature review of TFG gene mutations and associated phenotypes.
- Analysis of studies linking TFG function to ER-Golgi transport.
- Synthesis of evidence connecting ER dysfunction to neurodegeneration in TFG-related disorders.
Main Results:
- TFG mutations cause autosomal-dominant hereditary motor and sensory neuropathy, early-onset spastic paraplegia with optic atrophy and neuropathy, and dominant axonal Charcot-Marie-Tooth disease type 2.
- These mutations are associated with endoplasmic reticulum (ER) dysfunction.
- Evidence suggests a causal link between TFG mutations, ER homeostasis disruption, and neurodegeneration.
Conclusions:
- Mutations in TFG are a significant cause of a spectrum of neurodegenerative diseases.
- Endoplasmic reticulum (ER) dysfunction is a key pathogenic mechanism in TFG-related neurological disorders.
- Further research is needed to fully elucidate the precise pathogenetic mechanisms.
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