title: Spinocerebellar ataxia 35: novel mutations in TGM6 with clinical and genetic characterization.
abstract: OBJECTIVE
  To elucidate the clinical and cellular characteristics of spinocerebellar ataxia type 35 (SCA35), which is caused by mutations in the TGM6 gene encoding transglutaminase 6 (TG6), in a Taiwanese cohort.
  
  
  METHODS
  Mutations in TGM6 were ascertained in 109 unrelated probands of Chinese descent with molecularly unassigned SCA from 512 pedigrees, in whom mutations responsible for 15 other ataxia syndromes had been excluded. The clinical features of all patients with a TGM6 mutation were systematically analyzed. The biological consequences of the newly identified TGM6 mutations were investigated in HEK293 cells transfected with mutant complementary DNA constructs.
  
  
  RESULTS
  Two missense mutations (p.R111C and p.D510H) and one 3-base pair deletion (p.E574del) in TGM6 were identified. Among them, p.R111C and p.E574del were novel. The common features of SCA35 include a slowly progressive clinical course, trunk/limb ataxia, and hand tremors. The age at onset varies from adolescence to the fifth decade. Torticollis and intellectual impairment are rare manifestations. Brain MRI reveals diffuse cerebellar atrophy without involvement of the cerebral hemispheres or brainstem. The 3 mutations identified here attenuated the protein stability and catalytic activities of TG6.
  
  
  CONCLUSIONS
  SCA35 is an uncommon ataxia syndrome, accounting for 0.6% (3/512) of SCAs among the Han-Chinese descent in Taiwan. This study broadens the mutational spectrum of SCA35 and stresses the importance of TG6 in cerebellar functions.
authors.affiliation: From the Institute of Clinical Medicine (Y.-C.G.), National Yang-Ming University, Taipei; Department of Neurology (Y.-C. Liao, P.-C.T., Y.-C. Lee, B.-W.S.) and Brain Research Center (P.-C.T., Y.-C. Lee, B.-W.S.), National Yang-Ming University School of Medicine, 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; Department of Neurology (J.-J.L.), Chushang Show-Chwan Hospital, Nantou; Department of Neurology (J.-J.L.), Chung-Shan Medical University Hospital, Taichung; and Department of Neurology (Y.-C. Liao, P.-C.T., Y.-C. Lee, B.-W.S.), Taipei Veterans General Hospital, Taiwan.
authors.forename: Yuh-Cherng
authors.initials: YC
authors.lastname: Guo
authors.affiliation: From the Institute of Clinical Medicine (Y.-C.G.), National Yang-Ming University, Taipei; Department of Neurology (Y.-C. Liao, P.-C.T., Y.-C. Lee, B.-W.S.) and Brain Research Center (P.-C.T., Y.-C. Lee, B.-W.S.), National Yang-Ming University School of Medicine, 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; Department of Neurology (J.-J.L.), Chushang Show-Chwan Hospital, Nantou; Department of Neurology (J.-J.L.), Chung-Shan Medical University Hospital, Taichung; and Department of Neurology (Y.-C. Liao, P.-C.T., Y.-C. Lee, B.-W.S.), Taipei Veterans General Hospital, Taiwan.
authors.forename: Juei-Jueng
authors.initials: JJ
authors.lastname: Lin
authors.affiliation: From the Institute of Clinical Medicine (Y.-C.G.), National Yang-Ming University, Taipei; Department of Neurology (Y.-C. Liao, P.-C.T., Y.-C. Lee, B.-W.S.) and Brain Research Center (P.-C.T., Y.-C. Lee, B.-W.S.), National Yang-Ming University School of Medicine, 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; Department of Neurology (J.-J.L.), Chushang Show-Chwan Hospital, Nantou; Department of Neurology (J.-J.L.), Chung-Shan Medical University Hospital, Taichung; and Department of Neurology (Y.-C. Liao, P.-C.T., Y.-C. Lee, B.-W.S.), Taipei Veterans General Hospital, Taiwan.
authors.forename: Yi-Chu
authors.initials: YC
authors.lastname: Liao
authors.affiliation: From the Institute of Clinical Medicine (Y.-C.G.), National Yang-Ming University, Taipei; Department of Neurology (Y.-C. Liao, P.-C.T., Y.-C. Lee, B.-W.S.) and Brain Research Center (P.-C.T., Y.-C. Lee, B.-W.S.), National Yang-Ming University School of Medicine, 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; Department of Neurology (J.-J.L.), Chushang Show-Chwan Hospital, Nantou; Department of Neurology (J.-J.L.), Chung-Shan Medical University Hospital, Taichung; and Department of Neurology (Y.-C. Liao, P.-C.T., Y.-C. Lee, B.-W.S.), Taipei Veterans General Hospital, Taiwan.
authors.forename: Pei-Chien
authors.initials: PC
authors.lastname: Tsai
authors.affiliation: From the Institute of Clinical Medicine (Y.-C.G.), National Yang-Ming University, Taipei; Department of Neurology (Y.-C. Liao, P.-C.T., Y.-C. Lee, B.-W.S.) and Brain Research Center (P.-C.T., Y.-C. Lee, B.-W.S.), National Yang-Ming University School of Medicine, 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; Department of Neurology (J.-J.L.), Chushang Show-Chwan Hospital, Nantou; Department of Neurology (J.-J.L.), Chung-Shan Medical University Hospital, Taichung; and Department of Neurology (Y.-C. Liao, P.-C.T., Y.-C. Lee, B.-W.S.), Taipei Veterans General Hospital, Taiwan.
authors.forename: Yi-Chung
authors.initials: YC
authors.lastname: Lee
authors.affiliation: From the Institute of Clinical Medicine (Y.-C.G.), National Yang-Ming University, Taipei; Department of Neurology (Y.-C. Liao, P.-C.T., Y.-C. Lee, B.-W.S.) and Brain Research Center (P.-C.T., Y.-C. Lee, B.-W.S.), National Yang-Ming University School of Medicine, 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; Department of Neurology (J.-J.L.), Chushang Show-Chwan Hospital, Nantou; Department of Neurology (J.-J.L.), Chung-Shan Medical University Hospital, Taichung; and Department of Neurology (Y.-C. Liao, P.-C.T., Y.-C. Lee, B.-W.S.), Taipei Veterans General Hospital, Taiwan. bwsoong@ym.edu.tw ycli@vghtpe.gov.tw.
authors.forename: Bing-Wen
authors.initials: BW
authors.lastname: Soong
mesh_terms: D000328:Adult; D017668:Age of Onset; D001921:Brain / Q000473:pathology; D015331:Cohort Studies; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005192:Family Health; D005260:Female; D057809:HEK293 Cells / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D008607:Intellectual Disability / Q000209:etiology; D017827:Machado-Joseph Disease / Q000235:genetics* / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D020125:Mutation, Missense / Q000235:genetics*; D013624:Taiwan; D014103:Torticollis / Q000209:etiology; D014162:Transfection; D011503:Transglutaminases / Q000235:genetics* / Q000378:metabolism
chemical_list: C532876:TGM6 protein, human; D011503:Transglutaminases