title: A novel TFG mutation causes Charcot-Marie-Tooth disease type 2 and impairs TFG function.
abstract: OBJECTIVE
  To describe a novel mutation in TRK-fused gene (TFG) as a new cause of dominant axonal Charcot-Marie-Tooth disease (CMT) identified by exome sequencing and further characterized by in vitro functional studies.
  
  
  METHODS
  Exome sequencing and linkage analysis were utilized to investigate a large Taiwanese family with a dominantly inherited adult-onset motor and sensory axonal neuropathy in which mutations in common CMT2-implicated genes had been previously excluded. Functional effects of the mutant gene products were investigated in vitro.
  
  
  RESULTS
  Exome sequencing of 2 affected individuals in this family revealed a novel heterozygous mutation, c.806G>T (p.Gly269Val), in TFG that perfectly cosegregates with the CMT2 phenotype in all 27 family members. This mutation occurs at an evolutionarily conserved residue and is absent in the 1,140 ethnically matched control chromosomes. Genome-wide linkage study also supported its disease-causative role. Cell transfection studies showed that the TFG p.Gly269Val mutation increased the propensity of TFG proteins to form aggregates, resulting in sequestration of both mutant and wild-type TFG proteins and might thus deplete functional TFG molecules. The secreted Gaussia luciferase reporter assay demonstrated that inhibition of endogenous TFG compromised the protein secretion pathways, which could only be rescued by expressing wild-type TFG but not the p.Gly269Val altered proteins. TFG mutation was not found in 55 additional unrelated patients with CMT2, suggesting its rarity.
  
  
  CONCLUSIONS
  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.
authors.affiliation: From the Departments of Neurology (P.-C.T., K.-P.L., Y.-C. Liao, Y.-T.L., B.-W.S., Y.-C. Lee) and Radiology (H.-T.W.), Taipei Veterans General Hospital; Department of Neurology (K.-P.L., Y.-C. Liao, Y.-T.L., B.-W.S., Y.-C. Lee), Brain Research Center (P.-C.T., L.-S.K., M.-J.F., B.-W.S., Y.-C. Lee), Institute of Biomedical Informatics (Y.-H.H.), Center or Systems and Synthetic Biology (Y.-H.H., Y.-S.T.), Department of Life Sciences and Institute of Genome Sciences (L.-S.K., M.-J.F.), Genome Research Center (T.-T.L., L.-S.K.), and Institute of Neuroscience (B.-W.S.), National Yang-Ming University, Taipei; Neuroscience Laboratory (Y.-C.G.), Department of Neurology, China Medical University Hospital, Taichung; School of Medicine (Y.-C.G.), College of Medicine, China Medical University, Taichung; and Institute of Cellular and System Medicine (S.-F.Y.), National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Pei-Chien
authors.initials: PC
authors.lastname: Tsai
authors.affiliation: From the Departments of Neurology (P.-C.T., K.-P.L., Y.-C. Liao, Y.-T.L., B.-W.S., Y.-C. Lee) and Radiology (H.-T.W.), Taipei Veterans General Hospital; Department of Neurology (K.-P.L., Y.-C. Liao, Y.-T.L., B.-W.S., Y.-C. Lee), Brain Research Center (P.-C.T., L.-S.K., M.-J.F., B.-W.S., Y.-C. Lee), Institute of Biomedical Informatics (Y.-H.H.), Center or Systems and Synthetic Biology (Y.-H.H., Y.-S.T.), Department of Life Sciences and Institute of Genome Sciences (L.-S.K., M.-J.F.), Genome Research Center (T.-T.L., L.-S.K.), and Institute of Neuroscience (B.-W.S.), National Yang-Ming University, Taipei; Neuroscience Laboratory (Y.-C.G.), Department of Neurology, China Medical University Hospital, Taichung; School of Medicine (Y.-C.G.), College of Medicine, China Medical University, Taichung; and Institute of Cellular and System Medicine (S.-F.Y.), National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Yen-Hua
authors.initials: YH
authors.lastname: Huang
authors.affiliation: From the Departments of Neurology (P.-C.T., K.-P.L., Y.-C. Liao, Y.-T.L., B.-W.S., Y.-C. Lee) and Radiology (H.-T.W.), Taipei Veterans General Hospital; Department of Neurology (K.-P.L., Y.-C. Liao, Y.-T.L., B.-W.S., Y.-C. Lee), Brain Research Center (P.-C.T., L.-S.K., M.-J.F., B.-W.S., Y.-C. Lee), Institute of Biomedical Informatics (Y.-H.H.), Center or Systems and Synthetic Biology (Y.-H.H., Y.-S.T.), Department of Life Sciences and Institute of Genome Sciences (L.-S.K., M.-J.F.), Genome Research Center (T.-T.L., L.-S.K.), and Institute of Neuroscience (B.-W.S.), National Yang-Ming University, Taipei; Neuroscience Laboratory (Y.-C.G.), Department of Neurology, China Medical University Hospital, Taichung; School of Medicine (Y.-C.G.), College of Medicine, China Medical University, Taichung; and Institute of Cellular and System Medicine (S.-F.Y.), National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Yuh-Cherng
authors.initials: YC
authors.lastname: Guo
authors.affiliation: From the Departments of Neurology (P.-C.T., K.-P.L., Y.-C. Liao, Y.-T.L., B.-W.S., Y.-C. Lee) and Radiology (H.-T.W.), Taipei Veterans General Hospital; Department of Neurology (K.-P.L., Y.-C. Liao, Y.-T.L., B.-W.S., Y.-C. Lee), Brain Research Center (P.-C.T., L.-S.K., M.-J.F., B.-W.S., Y.-C. Lee), Institute of Biomedical Informatics (Y.-H.H.), Center or Systems and Synthetic Biology (Y.-H.H., Y.-S.T.), Department of Life Sciences and Institute of Genome Sciences (L.-S.K., M.-J.F.), Genome Research Center (T.-T.L., L.-S.K.), and Institute of Neuroscience (B.-W.S.), National Yang-Ming University, Taipei; Neuroscience Laboratory (Y.-C.G.), Department of Neurology, China Medical University Hospital, Taichung; School of Medicine (Y.-C.G.), College of Medicine, China Medical University, Taichung; and Institute of Cellular and System Medicine (S.-F.Y.), National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Hung-Ta
authors.initials: HT
authors.lastname: Wu
authors.affiliation: From the Departments of Neurology (P.-C.T., K.-P.L., Y.-C. Liao, Y.-T.L., B.-W.S., Y.-C. Lee) and Radiology (H.-T.W.), Taipei Veterans General Hospital; Department of Neurology (K.-P.L., Y.-C. Liao, Y.-T.L., B.-W.S., Y.-C. Lee), Brain Research Center (P.-C.T., L.-S.K., M.-J.F., B.-W.S., Y.-C. Lee), Institute of Biomedical Informatics (Y.-H.H.), Center or Systems and Synthetic Biology (Y.-H.H., Y.-S.T.), Department of Life Sciences and Institute of Genome Sciences (L.-S.K., M.-J.F.), Genome Research Center (T.-T.L., L.-S.K.), and Institute of Neuroscience (B.-W.S.), National Yang-Ming University, Taipei; Neuroscience Laboratory (Y.-C.G.), Department of Neurology, China Medical University Hospital, Taichung; School of Medicine (Y.-C.G.), College of Medicine, China Medical University, Taichung; and Institute of Cellular and System Medicine (S.-F.Y.), National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Kon-Ping
authors.initials: KP
authors.lastname: Lin
authors.affiliation: From the Departments of Neurology (P.-C.T., K.-P.L., Y.-C. Liao, Y.-T.L., B.-W.S., Y.-C. Lee) and Radiology (H.-T.W.), Taipei Veterans General Hospital; Department of Neurology (K.-P.L., Y.-C. Liao, Y.-T.L., B.-W.S., Y.-C. Lee), Brain Research Center (P.-C.T., L.-S.K., M.-J.F., B.-W.S., Y.-C. Lee), Institute of Biomedical Informatics (Y.-H.H.), Center or Systems and Synthetic Biology (Y.-H.H., Y.-S.T.), Department of Life Sciences and Institute of Genome Sciences (L.-S.K., M.-J.F.), Genome Research Center (T.-T.L., L.-S.K.), and Institute of Neuroscience (B.-W.S.), National Yang-Ming University, Taipei; Neuroscience Laboratory (Y.-C.G.), Department of Neurology, China Medical University Hospital, Taichung; School of Medicine (Y.-C.G.), College of Medicine, China Medical University, Taichung; and Institute of Cellular and System Medicine (S.-F.Y.), National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Yu-Shuen
authors.initials: YS
authors.lastname: Tsai
authors.affiliation: From the Departments of Neurology (P.-C.T., K.-P.L., Y.-C. Liao, Y.-T.L., B.-W.S., Y.-C. Lee) and Radiology (H.-T.W.), Taipei Veterans General Hospital; Department of Neurology (K.-P.L., Y.-C. Liao, Y.-T.L., B.-W.S., Y.-C. Lee), Brain Research Center (P.-C.T., L.-S.K., M.-J.F., B.-W.S., Y.-C. Lee), Institute of Biomedical Informatics (Y.-H.H.), Center or Systems and Synthetic Biology (Y.-H.H., Y.-S.T.), Department of Life Sciences and Institute of Genome Sciences (L.-S.K., M.-J.F.), Genome Research Center (T.-T.L., L.-S.K.), and Institute of Neuroscience (B.-W.S.), National Yang-Ming University, Taipei; Neuroscience Laboratory (Y.-C.G.), Department of Neurology, China Medical University Hospital, Taichung; School of Medicine (Y.-C.G.), College of Medicine, China Medical University, Taichung; and Institute of Cellular and System Medicine (S.-F.Y.), National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Yi-Chu
authors.initials: YC
authors.lastname: Liao
authors.affiliation: From the Departments of Neurology (P.-C.T., K.-P.L., Y.-C. Liao, Y.-T.L., B.-W.S., Y.-C. Lee) and Radiology (H.-T.W.), Taipei Veterans General Hospital; Department of Neurology (K.-P.L., Y.-C. Liao, Y.-T.L., B.-W.S., Y.-C. Lee), Brain Research Center (P.-C.T., L.-S.K., M.-J.F., B.-W.S., Y.-C. Lee), Institute of Biomedical Informatics (Y.-H.H.), Center or Systems and Synthetic Biology (Y.-H.H., Y.-S.T.), Department of Life Sciences and Institute of Genome Sciences (L.-S.K., M.-J.F.), Genome Research Center (T.-T.L., L.-S.K.), and Institute of Neuroscience (B.-W.S.), National Yang-Ming University, Taipei; Neuroscience Laboratory (Y.-C.G.), Department of Neurology, China Medical University Hospital, Taichung; School of Medicine (Y.-C.G.), College of Medicine, China Medical University, Taichung; and Institute of Cellular and System Medicine (S.-F.Y.), National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Yo-Tsen
authors.initials: YT
authors.lastname: Liu
authors.affiliation: From the Departments of Neurology (P.-C.T., K.-P.L., Y.-C. Liao, Y.-T.L., B.-W.S., Y.-C. Lee) and Radiology (H.-T.W.), Taipei Veterans General Hospital; Department of Neurology (K.-P.L., Y.-C. Liao, Y.-T.L., B.-W.S., Y.-C. Lee), Brain Research Center (P.-C.T., L.-S.K., M.-J.F., B.-W.S., Y.-C. Lee), Institute of Biomedical Informatics (Y.-H.H.), Center or Systems and Synthetic Biology (Y.-H.H., Y.-S.T.), Department of Life Sciences and Institute of Genome Sciences (L.-S.K., M.-J.F.), Genome Research Center (T.-T.L., L.-S.K.), and Institute of Neuroscience (B.-W.S.), National Yang-Ming University, Taipei; Neuroscience Laboratory (Y.-C.G.), Department of Neurology, China Medical University Hospital, Taichung; School of Medicine (Y.-C.G.), College of Medicine, China Medical University, Taichung; and Institute of Cellular and System Medicine (S.-F.Y.), National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Tze-Tze
authors.initials: TT
authors.lastname: Liu
authors.affiliation: From the Departments of Neurology (P.-C.T., K.-P.L., Y.-C. Liao, Y.-T.L., B.-W.S., Y.-C. Lee) and Radiology (H.-T.W.), Taipei Veterans General Hospital; Department of Neurology (K.-P.L., Y.-C. Liao, Y.-T.L., B.-W.S., Y.-C. Lee), Brain Research Center (P.-C.T., L.-S.K., M.-J.F., B.-W.S., Y.-C. Lee), Institute of Biomedical Informatics (Y.-H.H.), Center or Systems and Synthetic Biology (Y.-H.H., Y.-S.T.), Department of Life Sciences and Institute of Genome Sciences (L.-S.K., M.-J.F.), Genome Research Center (T.-T.L., L.-S.K.), and Institute of Neuroscience (B.-W.S.), National Yang-Ming University, Taipei; Neuroscience Laboratory (Y.-C.G.), Department of Neurology, China Medical University Hospital, Taichung; School of Medicine (Y.-C.G.), College of Medicine, China Medical University, Taichung; and Institute of Cellular and System Medicine (S.-F.Y.), National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Lung-Sen
authors.initials: LS
authors.lastname: Kao
authors.affiliation: From the Departments of Neurology (P.-C.T., K.-P.L., Y.-C. Liao, Y.-T.L., B.-W.S., Y.-C. Lee) and Radiology (H.-T.W.), Taipei Veterans General Hospital; Department of Neurology (K.-P.L., Y.-C. Liao, Y.-T.L., B.-W.S., Y.-C. Lee), Brain Research Center (P.-C.T., L.-S.K., M.-J.F., B.-W.S., Y.-C. Lee), Institute of Biomedical Informatics (Y.-H.H.), Center or Systems and Synthetic Biology (Y.-H.H., Y.-S.T.), Department of Life Sciences and Institute of Genome Sciences (L.-S.K., M.-J.F.), Genome Research Center (T.-T.L., L.-S.K.), and Institute of Neuroscience (B.-W.S.), National Yang-Ming University, Taipei; Neuroscience Laboratory (Y.-C.G.), Department of Neurology, China Medical University Hospital, Taichung; School of Medicine (Y.-C.G.), College of Medicine, China Medical University, Taichung; and Institute of Cellular and System Medicine (S.-F.Y.), National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Shaw-Fang
authors.initials: SF
authors.lastname: Yet
authors.affiliation: From the Departments of Neurology (P.-C.T., K.-P.L., Y.-C. Liao, Y.-T.L., B.-W.S., Y.-C. Lee) and Radiology (H.-T.W.), Taipei Veterans General Hospital; Department of Neurology (K.-P.L., Y.-C. Liao, Y.-T.L., B.-W.S., Y.-C. Lee), Brain Research Center (P.-C.T., L.-S.K., M.-J.F., B.-W.S., Y.-C. Lee), Institute of Biomedical Informatics (Y.-H.H.), Center or Systems and Synthetic Biology (Y.-H.H., Y.-S.T.), Department of Life Sciences and Institute of Genome Sciences (L.-S.K., M.-J.F.), Genome Research Center (T.-T.L., L.-S.K.), and Institute of Neuroscience (B.-W.S.), National Yang-Ming University, Taipei; Neuroscience Laboratory (Y.-C.G.), Department of Neurology, China Medical University Hospital, Taichung; School of Medicine (Y.-C.G.), College of Medicine, China Medical University, Taichung; and Institute of Cellular and System Medicine (S.-F.Y.), National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Ming-Ji
authors.initials: MJ
authors.lastname: Fann
authors.affiliation: From the Departments of Neurology (P.-C.T., K.-P.L., Y.-C. Liao, Y.-T.L., B.-W.S., Y.-C. Lee) and Radiology (H.-T.W.), Taipei Veterans General Hospital; Department of Neurology (K.-P.L., Y.-C. Liao, Y.-T.L., B.-W.S., Y.-C. Lee), Brain Research Center (P.-C.T., L.-S.K., M.-J.F., B.-W.S., Y.-C. Lee), Institute of Biomedical Informatics (Y.-H.H.), Center or Systems and Synthetic Biology (Y.-H.H., Y.-S.T.), Department of Life Sciences and Institute of Genome Sciences (L.-S.K., M.-J.F.), Genome Research Center (T.-T.L., L.-S.K.), and Institute of Neuroscience (B.-W.S.), National Yang-Ming University, Taipei; Neuroscience Laboratory (Y.-C.G.), Department of Neurology, China Medical University Hospital, Taichung; School of Medicine (Y.-C.G.), College of Medicine, China Medical University, Taichung; and Institute of Cellular and System Medicine (S.-F.Y.), National Health Research Institutes, Zhunan, Taiwan. ycli@vghtpe.gov.tw bwsoong@ym.edu.tw.
authors.forename: Bing-Wen
authors.initials: BW
authors.lastname: Soong
authors.affiliation: From the Departments of Neurology (P.-C.T., K.-P.L., Y.-C. Liao, Y.-T.L., B.-W.S., Y.-C. Lee) and Radiology (H.-T.W.), Taipei Veterans General Hospital; Department of Neurology (K.-P.L., Y.-C. Liao, Y.-T.L., B.-W.S., Y.-C. Lee), Brain Research Center (P.-C.T., L.-S.K., M.-J.F., B.-W.S., Y.-C. Lee), Institute of Biomedical Informatics (Y.-H.H.), Center or Systems and Synthetic Biology (Y.-H.H., Y.-S.T.), Department of Life Sciences and Institute of Genome Sciences (L.-S.K., M.-J.F.), Genome Research Center (T.-T.L., L.-S.K.), and Institute of Neuroscience (B.-W.S.), National Yang-Ming University, Taipei; Neuroscience Laboratory (Y.-C.G.), Department of Neurology, China Medical University Hospital, Taichung; School of Medicine (Y.-C.G.), College of Medicine, China Medical University, Taichung; and Institute of Cellular and System Medicine (S.-F.Y.), National Health Research Institutes, Zhunan, Taiwan. ycli@vghtpe.gov.tw bwsoong@ym.edu.tw.
authors.forename: Yi-Chung
authors.initials: YC
authors.lastname: Lee
mesh_terms: D000328:Adult; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D059472:Exome; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D013624:Taiwan; D033921:Vesicular Transport Proteins
chemical_list: D011506:Proteins; C096163:TFG protein, human; D033921:Vesicular Transport Proteins