title: DCTN1 p.K56R in progressive supranuclear palsy.
abstract: Mutations in dynactin DCTN1 (p150(glued)) have previously been linked to familial motor neuron disease or Perry syndrome (PS) consisting of depression, parkinsonism and hypoventilation.
  
  
  
  We sequenced DCTN1 in 636 Caucasian patients with parkinsonism (Parkinson's disease and Parkinson-plus syndromes) and 508 healthy controls. Variants (MAF < 0.01) were subsequently genotyped in Caucasian (1360 cases and 1009 controls) and Asian cohorts (1046 cases and 830 controls), and the functional implications of pathogenic variants were assessed.
  
  
  
  We identified 17 rare variants leading to non-synonymous amino-acid substitutions. Four of the variants were only observed in control subjects, four in both cases and controls and the remaining nine in cases only. One of the variants, DCTN1 p.K56R, was present in two patients with progressive supranuclear palsy (PSP) with a shared minimal 2.2 Mb haplotype. Both subjects have parkinsonism as the most prominent symptom with abnormal ocular movements, moderate cognitive impairment and little to no l-dopa response. Neither subject presents with depression, central hypoventilation or weight loss. For one of the subjects MRI shows symmetrical atrophy of temporal and frontoparietal lobes. In HEK293 cells mutant p150(glued) (p.K56R) shows less affinity for microtubules than wild-type, with a more diffuse cytoplasmic distribution.
  
  
  
  We have identified DCTN1 p.K56R in patients with PSP. This variant is immediately adjacent to the N-terminal p150(glued) 'CAP-Gly' domain, affects a highly conserved amino acid and alters the protein's affinity to microtubules and its cytoplasmic distribution.
authors.affiliation: Centre for Applied Neurogenetics, Djavad Mowafaghian Centre for Brain Health, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neurology, St. Olav's Hospital, Trondheim, Norway.
authors.forename: Emil K
authors.initials: EK
authors.lastname: Gustavsson
authors.affiliation: Centre for Applied Neurogenetics, Djavad Mowafaghian Centre for Brain Health, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Joanne
authors.initials: J
authors.lastname: Trinh
authors.affiliation: Centre for Applied Neurogenetics, Djavad Mowafaghian Centre for Brain Health, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Guella
authors.affiliation: Centre for Applied Neurogenetics, Djavad Mowafaghian Centre for Brain Health, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Chelsea
authors.initials: C
authors.lastname: Szu-Tu
authors.affiliation: Centre for Applied Neurogenetics, Djavad Mowafaghian Centre for Brain Health, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Jaskaran
authors.initials: J
authors.lastname: Khinda
authors.affiliation: Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chin-Hsien
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Ruey-Meei
authors.initials: RM
authors.lastname: Wu
authors.affiliation: Pacific Parkinson's Research Centre, Department of Medicine (Neurology), University of British Columbia Vancouver, BC, Canada.
authors.forename: Jon
authors.initials: J
authors.lastname: Stoessl
authors.affiliation: Pacific Parkinson's Research Centre, Department of Medicine (Neurology), University of British Columbia Vancouver, BC, Canada.
authors.forename: Silke
authors.initials: S
authors.lastname: Appel-Cresswell
authors.affiliation: Pacific Parkinson's Research Centre, Department of Medicine (Neurology), University of British Columbia Vancouver, BC, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: McKeown
authors.affiliation: Division of Neurology, University of Saskatchewan and Saskatoon Health Region, Saskatoon, SK, Canada.
authors.forename: Alex
authors.initials: A
authors.lastname: Rajput
authors.affiliation: Division of Neurology, University of Saskatchewan and Saskatoon Health Region, Saskatoon, SK, Canada.
authors.forename: Ali H
authors.initials: AH
authors.lastname: Rajput
authors.affiliation: Department of Occupational Medicine and Public Health, The Faroese Hospital System, Torshavn, Faroe Islands.
authors.forename: Maria Skaalum
authors.initials: MS
authors.lastname: Petersen
authors.affiliation: Department of Neurology, Clinical Research Institute and Movement Disorder Center, Seoul National University Hospital, Seoul, South Korea.
authors.forename: Beom S
authors.initials: BS
authors.lastname: Jeon
authors.affiliation: Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neurology, St. Olav's Hospital, Trondheim, Norway.
authors.forename: Jan O
authors.initials: JO
authors.lastname: Aasly
authors.affiliation: Centre for Applied Neurogenetics, Djavad Mowafaghian Centre for Brain Health, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada. Electronic address: mfarrer@can.ubc.ca.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Farrer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000072159:Dynactin Complex / Q000235:genetics*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics; D020734:Parkinsonian Disorders / Q000235:genetics*; D010641:Phenotype; D013494:Supranuclear Palsy, Progressive / Q000235:genetics* / Q000503:physiopathology; D055815:Young Adult
chemical_list: C000606360:DCTN1 protein, human; D000072159:Dynactin Complex
keywords: DCTN1; Microtubule; Mutation; Parkinsonism; Progressive supranuclear palsy; p150Glued