Pei-Chien Tsai1, Yen-Hua Huang1, Yuh-Cherng Guo1, Hung-Ta Wu1, Kon-Ping Lin1, Yu-Shuen Tsai1, Yi-Chu Liao1, Yo-Tsen Liu1, Tze-Tze Liu1, Lung-Sen Kao1, Shaw-Fang Yet1, Ming-Ji Fann1, Bing-Wen Soong2, Yi-Chung Lee2. 1. 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. 2. 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.
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. CONCLUSION: 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.
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 TFGp.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. CONCLUSION: 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: A Catania; R Battini; T Pippucci; R Pasquariello; M L Chiapparini; M Seri; B Garavaglia; G Zorzi; N Nardocci; D Ghezzi; V Tiranti Journal: Neurogenetics Date: 2018-07-03 Impact factor: 2.660
Authors: Jennifer L Peotter; Iryna Pustova; Molly M Lettman; Shalini Shatadal; Mazdak M Bradberry; Allison D Winter-Reed; Maya Charan; Erin E Sharkey; James R Alvin; Alyssa M Bren; Annika K Oie; Edwin R Chapman; M Shahriar Salamat; Anjon Audhya Journal: Proc Natl Acad Sci U S A Date: 2022-09-26 Impact factor: 12.779
Authors: Janine McCaughey; Victoria J Miller; Nicola L Stevenson; Anna K Brown; Annika Budnik; Kate J Heesom; Dominic Alibhai; David J Stephens Journal: Cell Rep Date: 2016-05-12 Impact factor: 9.423