title: Recessive mutations in the α3 (VI) collagen gene COL6A3 cause early-onset isolated dystonia.
abstract: Isolated dystonia is a disorder characterized by involuntary twisting postures arising from sustained muscle contractions. Although autosomal-dominant mutations in TOR1A, THAP1, and GNAL have been found in some cases, the molecular mechanisms underlying isolated dystonia are largely unknown. In addition, although emphasis has been placed on dominant isolated dystonia, the disorder is also transmitted as a recessive trait, for which no mutations have been defined. Using whole-exome sequencing in a recessive isolated dystonia-affected kindred, we identified disease-segregating compound heterozygous mutations in COL6A3, a collagen VI gene associated previously with muscular dystrophy. Genetic screening of a further 367 isolated dystonia subjects revealed two additional recessive pedigrees harboring compound heterozygous mutations in COL6A3. Strikingly, all affected individuals had at least one pathogenic allele in exon 41, including an exon-skipping mutation that induced an in-frame deletion. We tested the hypothesis that disruption of this exon is pathognomonic for isolated dystonia by inducing a series of in-frame deletions in zebrafish embryos. Consistent with our human genetics data, suppression of the exon 41 ortholog caused deficits in axonal outgrowth, whereas suppression of other exons phenocopied collagen deposition mutants. All recessive mutation carriers demonstrated early-onset segmental isolated dystonia without muscular disease. Finally, we show that Col6a3 is expressed in neurons, with relevant mRNA levels detectable throughout the adult mouse brain. Taken together, our data indicate that loss-of-function mutations affecting a specific region of COL6A3 cause recessive isolated dystonia with underlying neurodevelopmental deficits and highlight the brain extracellular matrix as a contributor to dystonia pathogenesis.
authors.affiliation: Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany; Department of Neurology and Neurological Sciences and Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Palo Alto, CA 94304, USA; Institut für Humangenetik, Helmholtz Zentrum München, 85764 Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Zech
authors.affiliation: Department of Neurology and Neurological Sciences and Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Palo Alto, CA 94304, USA.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Lam
authors.affiliation: Center for Human Disease Modeling, Department of Cell Biology, Duke University, Durham, NC 27710, USA.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Francescatto
authors.affiliation: Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany; Institut für Humangenetik, Helmholtz Zentrum München, 85764 Munich, Germany; Institut für Humangenetik, Technische Universität München, 81675 Munich, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Schormair
authors.affiliation: Institut für Humangenetik, Helmholtz Zentrum München, 85764 Munich, Germany.
authors.forename: Aaro V
authors.initials: AV
authors.lastname: Salminen
authors.affiliation: Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Jochim
authors.affiliation: Institut für Humangenetik, Helmholtz Zentrum München, 85764 Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.affiliation: Institut für Humangenetik, Helmholtz Zentrum München, 85764 Munich, Germany; Institut für Humangenetik, Technische Universität München, 81675 Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lichtner
authors.affiliation: Institute of Epidemiology II, Helmholtz Zentrum München, 85764 Munich, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Peters
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München, 85764 Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.affiliation: John Walton Centre for Muscular Dystrophy Research, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
authors.affiliation: Institut für Humangenetik, Helmholtz Zentrum München, 85764 Munich, Germany; Institut für Humangenetik, Technische Universität München, 81675 Munich, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Haslinger
authors.affiliation: Center for Human Disease Modeling, Department of Cell Biology, Duke University, Durham, NC 27710, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.affiliation: Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany; Department of Neurology and Neurological Sciences and Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Palo Alto, CA 94304, USA; Institut für Humangenetik, Helmholtz Zentrum München, 85764 Munich, Germany; Munich Cluster for Systems Neurology, SyNergy, 81377 Munich, Germany. Electronic address: winkelmann@stanford.edu.
authors.forename: Juliane
authors.initials: J
authors.lastname: Winkelmann
mesh_terms: D000818:Animals; D001483:Base Sequence; D024142:Collagen Type VI / Q000235:genetics*; D019295:Computational Biology; D004252:DNA Mutational Analysis; D020821:Dystonic Disorders / Q000235:genetics* / Q000473:pathology*; D059472:Exome / Q000235:genetics; D005808:Genes, Recessive; D005820:Genetic Testing; D014644:Genetic Variation; D017403:In Situ Hybridization; D008279:Magnetic Resonance Imaging; D051379:Mice; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D015027:Zebrafish / Q000235:genetics
chemical_list: D024142:Collagen Type VI