A novel
            <i>TFG</i>
            mutation causes Charcot-Marie-Tooth disease type 2 and impairs TFG function

Tsai, Pei Chien; Huang, Yen Hua; Guo, Yuh Cherng; Wu, Hsiang Ling; Lin, Kon Ping; Tsai, Yu Shuen; Liao, Yi‐Chu; Liu, Yo Tsen; Liu, Tze Tze; Kao, Lung‐Sen; Yet, Shaw Fang; Fann, Ming Ji; Soong, Bing Wen; Lee, Yi‐Chung

doi:10.1212/wnl.0000000000000758

Cited by 41 publications

(72 citation statements)

References 23 publications

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“…On the other hand, TFG was recently identified as a causative gene for several neurodegenerative diseases, such as hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) 6–8 , the axonal type of Charcot-Marie-Tooth disease 9 and hereditary spastic paraplegia (HSP) 10–12 . Among HMSN-P patients, high incidences of diabetes mellitus and dyslipidemia have been reported 13 , yet nothing is known about the role of TFG in the regulation of glucose or lipid metabolism.…”

Section: Introductionmentioning

confidence: 99%

Trk-fused gene (TFG) regulates pancreatic β cell mass and insulin secretory activity

Yamamotoya

Nakatsu

Kushiyama

et al. 2017

Sci Rep

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The Trk-fused gene (TFG) is reportedly involved in the process of COPII-mediated vesicle transport and missense mutations in TFG cause several neurodegenerative diseases including hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P). The high coincidence ratio between HMSN-P and diabetes mellitus suggests TFG to have an important role(s) in glucose homeostasis. To examine this possibility, β-cell specific TFG knockout mice (βTFG KO) were generated. Interestingly, βTFG KO displayed marked glucose intolerance with reduced insulin secretion. Immunohistochemical analysis revealed smaller β-cell masses in βTFG KO than in controls, likely attributable to diminished β-cell proliferation. Consistently, β-cell expansion in response to a high-fat, high-sucrose (HFHS) diet was significantly impaired in βTFG KO. Furthermore, glucose-induced insulin secretion was also markedly impaired in islets isolated from βTFG KO. Electron microscopic observation revealed endoplasmic reticulum (ER) dilatation, suggestive of ER stress, and smaller insulin crystal diameters in β-cells of βTFG KO. Microarray gene expression analysis indicated downregulation of NF-E2 related factor 2 (Nrf2) and its downstream genes in TFG depleted islets. Collectively, TFG in pancreatic β-cells plays a vital role in maintaining both the mass and function of β-cells, and its dysfunction increases the tendency to develop glucose intolerance.

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Section: Introductionmentioning

confidence: 99%

Trk-fused gene (TFG) regulates pancreatic β cell mass and insulin secretory activity

Yamamotoya

Nakatsu

Kushiyama

et al. 2017

Sci Rep

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“…Further genetic and phenotypic classification of CMT2 has grown to more than 20 subtypes [Murphy et al., ]. Causative genes have been continuously updated to be the novel underlying cause of CMT2, such as: DYNC1H1 (MIM #600112), DHTKD1 (MIM #614984), HINT1 (MIM #601314), MT‐ATP6 (MIM #516060), MARS (MIM #156560), HARS (MIM #142810), HADHB (MIM #143450), TFG (MIM #602498), and DNAJB2 (MIM #604139) [Weedon et al., ; Pitceathly et al., ; Xu et al., ; Zimoń et al., ; Gonzalez et al., ; Hong et al., ; Vester et al., ; Gess et al., ; Tsai et al., ]. Despite novel gene identification, considerable CMT2 patients still wait for a test to uncover genetic cause.…”

Section: Introductionmentioning

confidence: 99%

DGAT2Mutation in a Family with Autosomal-Dominant Early-Onset Axonal Charcot-Marie-Tooth Disease

et al. 2016

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Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy and is a genetically and clinically heterogeneous disorder. We examined a Korean family in which two individuals had an autosomal-dominant axonal CMT with early-onset, sensory ataxia, tremor, and slow disease progression. Pedigree analysis and exome sequencing identified a de novo missense mutation (p.Y223H) in the diacylglycerol O-acyltransferase 2 (DGAT2) gene. DGAT2 encodes an endoplasmic reticulum-mitochondrial-associated membrane protein, acyl-CoA:diacylglycerol acyltransferase, which catalyzes the final step of the triglyceride (TG) biosynthesis pathway. The patient showed consistently decreased serum TG levels, and overexpression of the mutant DGAT2 significantly inhibited the proliferation of mouse motor neuron cells. Moreover, the variant form of human DGAT2 inhibited the axonal branching in the peripheral nervous system of zebrafish. We suggest that mutation of DGAT2 is the novel underlying cause of an autosomal-dominant axonal CMT2 neuropathy. This study will help provide a better understanding of the pathophysiology of axonal CMT and contribute to the molecular diagnostics of peripheral neuropathies.

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“…It is well known that CMT is a highly heterogeneous disorder. Most CMT patients show a slowly progressive course and some CMT patients have a late age of onset (Tsai et al., ); therefore, to exclude individuals with mild syndrome, 500 unrelated elderly individuals (≥ 65 years old) without histories of CMT were selected as controls. Written informed consent was obtained from all of the subjects or their guardians.…”

Section: Methodsmentioning

confidence: 99%

Identification and functional characterization of two missense mutations in NDRG1 associated with Charcot‐Marie‐Tooth disease type 4D

Liu

et al. 2017

Human Mutation

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Charcot-Marie-Tooth disease type 4D (CMT4D) is an autosomal-recessive demyelinating form of CMT characterized by a severe distal motor and sensory neuropathy. NDRG1 is the causative gene for CMT4D. To date, only four mutations in NDRG1 -c.442C>T (p.Arg148*), c.739delC (p.His247Thrfs*74), c.538-1G>A, and duplication of exons 6-8-have been described in CMT4D patients. Here, using targeted next-generation sequencing examination, we identified for the first time two homozygous missense variants in NDRG1, c.437T>C (p.Leu146Pro) and c.701G>A (p.Arg234Gln), in two Chinese CMT families with consanguineous histories. Further functional studies were performed to characterize the biological effects of these variants. Cell culture transfection studies showed that mutant NDRG1 carrying p.Leu146Pro, p.Arg148*, or p.Arg234Gln variant degraded faster than wild-type NDRG1, resulting in lower protein levels. Live cell confocal microscopy and coimmunoprecipitation analysis indicated that these variants did not disrupt the interaction between NDRG1 and Rab4a protein. However, NDRG1-knockdown cells expressing mutant NDRG1 displayed enlarged Rab4a-positive compartments. Moreover, mutant NDRG1 could not enhance the uptake of DiI-LDL or increase the fraction of low-density lipoprotein receptor on the cell surface. Taken together, our study described two missense mutations in NDRG1 and emphasized the important role of NDRG1 in intracellular protein trafficking.

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A novel TFG mutation causes Charcot-Marie-Tooth disease type 2 and impairs TFG function

Abstract: This study identifies a new cause of dominant CMT2 and highlights the importance of TFG in the protein secretory pathways that are essential for proper functioning of the human peripheral nervous system.

Cited by 41 publications

References 23 publications

Trk-fused gene (TFG) regulates pancreatic β cell mass and insulin secretory activity

Trk-fused gene (TFG) regulates pancreatic β cell mass and insulin secretory activity

DGAT2Mutation in a Family with Autosomal-Dominant Early-Onset Axonal Charcot-Marie-Tooth Disease

Identification and functional characterization of two missense mutations in NDRG1 associated with Charcot‐Marie‐Tooth disease type 4D

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