title: The role of mutations in COL6A3 in isolated dystonia.
abstract: Specific mutations in COL6A3 have recently been reported as the cause of isolated recessive dystonia, which is a rare movement disorder. In all patients, at least one mutation was located in Exons 41 and 42. In an attempt to replicate these findings, we assessed by direct sequencing the frequency of rare variants in Exons 41 and 42 of COL6A3 in 955 patients with isolated or combined dystonia or with another movement disorder with dystonic features. We identified nine heterozygous carriers of rare variants including five different missense mutations and an extremely rare synonymous variant. In these nine patients, we sequenced the remaining 41 coding exons of COL6A3 to test for a second mutation in the compound heterozygous state. In only one of them, a second rare variant was identified (Thr732Met + Pro3082Arg). Of note, this patient had been diagnosed with Parkinson´s disease (with dystonic posturing) due to homozygous PINK1 mutations. The COL6A3 mutations clearly did not segregate with the disease in the four affected siblings of this family. Further, there was no indication for a disease-modifying effect of the COL6A3 mutations since disease severity or age at onset did not correlate with the number of COL6A3 mutated alleles in this family. In conjunction with the relatively high frequency of homozygous carriers of reported mutations in publically available databases, our data call a causal role for variants in COL6A3 in isolated dystonia into question.
authors.affiliation: Institute of Neurogenetics, University of Lübeck; Ratzeburger Allee 160, 23538, Lübeck, Germany. katja.lohmann@neuro.uni-luebeck.de.
authors.forename: Katja
authors.initials: K
authors.lastname: Lohmann
authors.affiliation: Institute of Neurogenetics, University of Lübeck; Ratzeburger Allee 160, 23538, Lübeck, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Schlicht
authors.affiliation: Department of Neurology, Belgrade University, 11000, Belgrade, Serbia.
authors.forename: Marina
authors.initials: M
authors.lastname: Svetel
authors.affiliation: Institute of Neurogenetics, University of Lübeck; Ratzeburger Allee 160, 23538, Lübeck, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Hinrichs
authors.affiliation: Institute of Neurogenetics, University of Lübeck; Ratzeburger Allee 160, 23538, Lübeck, Germany.|Department for Paediatric and Adult Movement Disorders and Neuropsychiatry, Institute of Neurogenetics, University of Lübeck, 23538, Lübeck, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Zittel
authors.affiliation: Institute of Neurogenetics, University of Lübeck; Ratzeburger Allee 160, 23538, Lübeck, Germany.|Department of Neurology, University of Lübeck, 23538, Lübeck, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Graf
authors.affiliation: Institute of Neurogenetics, University of Lübeck; Ratzeburger Allee 160, 23538, Lübeck, Germany.
authors.forename: Thora
authors.initials: T
authors.lastname: Lohnau
authors.affiliation: Institute of Neurogenetics, University of Lübeck; Ratzeburger Allee 160, 23538, Lübeck, Germany.|Kurt Singer Institute for Music Physiology and Musicians' Health, Hanns Eisler School of Music Berlin, 10117, Berlin, Germany.|Interdisciplinary Competence Center Musicians' Medicine, Charité, University Medicine Berlin, 13353, Berlin, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Schmidt
authors.affiliation: Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, CIBERNED, 41013, Seville, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Mir
authors.affiliation: Department of Neurology, Charité, University Medicine Berlin, 13353, Berlin, Germany.
authors.forename: Patricia
authors.initials: P
authors.lastname: Krause
authors.affiliation: Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, Toronto, ON, M5T 2S8, Canada.
authors.forename: Antony E
authors.initials: AE
authors.lastname: Lang
authors.affiliation: Institute of Music Physiology and Musicians' Medicine, Hanover University of Music, Drama and Media, 30175, Hanover, Germany.|Institute of Musicians´ Medicine, University of Music, 01069, Dresden, Germany.
authors.forename: Hans-Christian
authors.initials: HC
authors.lastname: Jabusch
authors.affiliation: Department of Neurology, University of Rostock, 18147, Rostock, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Wolters
authors.affiliation: Department of Neurology, University of Rostock, 18147, Rostock, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kamm
authors.affiliation: Department of Neurology, Christian Albrechts University, 24105, Kiel, Germany.
authors.forename: Kirsten E
authors.initials: KE
authors.lastname: Zeuner
authors.affiliation: Institute of Music Physiology and Musicians' Medicine, Hanover University of Music, Drama and Media, 30175, Hanover, Germany.
authors.forename: Eckart
authors.initials: E
authors.lastname: Altenmüller
authors.affiliation: School of Biological Sciences, University of the Punjab, Quaid-i-Azam Campus, Lahore, 54590, Pakistan.
authors.forename: Sadaf
authors.initials: S
authors.lastname: Naz
authors.affiliation: Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea.
authors.forename: Sun Ju
authors.initials: SJ
authors.lastname: Chung
authors.affiliation: Department of Neurology, Belgrade University, 11000, Belgrade, Serbia.
authors.forename: Vladimir S
authors.initials: VS
authors.lastname: Kostic
authors.affiliation: Institute of Neurogenetics, University of Lübeck; Ratzeburger Allee 160, 23538, Lübeck, Germany.|Department for Paediatric and Adult Movement Disorders and Neuropsychiatry, Institute of Neurogenetics, University of Lübeck, 23538, Lübeck, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Münchau
authors.affiliation: Department of Neurology, Charité, University Medicine Berlin, 13353, Berlin, Germany.
authors.forename: Andrea A
authors.initials: AA
authors.lastname: Kühn
authors.affiliation: Institute of Neurogenetics, University of Lübeck; Ratzeburger Allee 160, 23538, Lübeck, Germany.|Department of Neurology, University of Lübeck, 23538, Lübeck, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Brüggemann
authors.affiliation: Institute of Neurogenetics, University of Lübeck; Ratzeburger Allee 160, 23538, Lübeck, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
mesh_terms: D000328:Adult; D000368:Aged; D024142:Collagen Type VI / Q000235:genetics*; D004252:DNA Mutational Analysis; D020821:Dystonic Disorders / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree
chemical_list: C000601102:COL6A3 protein, human; D024142:Collagen Type VI
keywords: COL6A3; Dystonia; Exome sequencing; Validation