TY - JOUR
T1 - TFG-related neurologic disorders
T2 - New insights into relationships between endoplasmic reticulum and neurodegeneration
AU - Yagi, Takuya
AU - Ito, Daisuke
AU - Suzuki, Norihiro
N1 - Publisher Copyright:
© 2016 American Association of Neuropathologists, Inc. All rights reserved.
PY - 2016/4
Y1 - 2016/4
N2 - 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.
AB - 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.
KW - Charcot-Marie-Tooth disease
KW - Endoplasmic reticulum
KW - Neurodegeneration
KW - Spastic paraplegia
KW - Tropomyosin-receptor kinase fused gene (TFG)
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U2 - 10.1093/jnen/nlw009
DO - 10.1093/jnen/nlw009
M3 - Review article
C2 - 26945032
AN - SCOPUS:84961943348
VL - 75
SP - 299
EP - 305
JO - Journal of Neuropathology and Experimental Neurology
JF - Journal of Neuropathology and Experimental Neurology
SN - 0022-3069
IS - 4
ER -