title: Haploinsufficiency of KMT2B, Encoding the Lysine-Specific Histone Methyltransferase 2B, Results in Early-Onset Generalized Dystonia.
abstract: Early-onset generalized dystonia represents the severest form of dystonia, a hyperkinetic movement disorder defined by involuntary twisting postures. Although frequently transmitted as a single-gene trait, the molecular basis of dystonia remains largely obscure. By whole-exome sequencing a parent-offspring trio in an Austrian kindred affected by non-familial early-onset generalized dystonia, we identified a dominant de novo frameshift mutation, c.6406delC (p.Leu2136Serfs∗17), in KMT2B, encoding a lysine-specific methyltransferase involved in transcriptional regulation via post-translational modification of histones. Whole-exome-sequencing-based exploration of a further 30 German-Austrian individuals with early-onset generalized dystonia uncovered another three deleterious mutations in KMT2B-one de novo nonsense mutation (c.1633C>T [p.Arg545∗]), one de novo essential splice-site mutation (c.7050-2A>G [p.Phe2321Serfs∗93]), and one inherited nonsense mutation (c.2428C>T [p.Gln810∗]) co-segregating with dystonia in a three-generation kindred. Each of the four mutations was predicted to mediate a loss-of-function effect by introducing a premature termination codon. Suggestive of haploinsufficiency, we found significantly decreased total mRNA levels of KMT2B in mutant fibroblasts. The phenotype of individuals with KMT2B loss-of-function mutations was dominated by childhood lower-limb-onset generalized dystonia, and the family harboring c.2428C>T (p.Gln810∗) showed variable expressivity. In most cases, dystonic symptoms were accompanied by heterogeneous non-motor features. Independent support for pathogenicity of the mutations comes from the observation of high rates of dystonic presentations in KMT2B-involving microdeletion syndromes. Our findings thus establish generalized dystonia as the human phenotype associated with haploinsufficiency of KMT2B. Moreover, we provide evidence for a causative role of disordered histone modification, chromatin states, and transcriptional deregulation in dystonia pathogenesis.
authors.affiliation: Institut für Neurogenomik, Helmholtz Zentrum München, 85764 Munich, Germany; Klinik und Poliklinik für Neurologie, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Zech
authors.affiliation: Department of Neurology, Medical University Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Boesch
authors.affiliation: Dr. von Haunersches Kinderspital, Ludwig-Maximilians-Universität München, 80337 Munich, Germany.
authors.forename: Esther M
authors.initials: EM
authors.lastname: Maier
authors.affiliation: Dr. von Haunersches Kinderspital, Ludwig-Maximilians-Universität München, 80337 Munich, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Borggraefe
authors.affiliation: Dr. von Haunersches Kinderspital, Ludwig-Maximilians-Universität München, 80337 Munich, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Vill
authors.affiliation: Institute of Medical Genetics, Medical School of Vienna, 1090 Vienna, Austria.
authors.forename: Franco
authors.initials: F
authors.lastname: Laccone
authors.affiliation: Krankenhaus der Barmherzigen Schwestern Linz, 4020 Linz, Austria.
authors.forename: Veronika
authors.initials: V
authors.lastname: Pilshofer
authors.affiliation: Klinik und Poliklinik für Neurologie, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany; Schön Klinik München Schwabing, 80804 Munich, Germany.
authors.forename: Andres
authors.initials: A
authors.lastname: Ceballos-Baumann
authors.affiliation: Institut für Humangenetik, Technische Universität München, 81675 Munich, Germany.
authors.forename: Bader
authors.initials: B
authors.lastname: Alhaddad
authors.affiliation: Institut für Humangenetik, Helmholtz Zentrum München, 85764 Munich, Germany.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Berutti
authors.affiliation: Department of Neurology, Medical University Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Werner
authors.initials: W
authors.lastname: Poewe
authors.affiliation: Institut für Humangenetik, Technische Universität München, 81675 Munich, Germany; Institut für Humangenetik, Helmholtz Zentrum München, 85764 Munich, Germany; Devision of Molecular Genetics, Universitätsklinikum Tübingen, 72076 Tübingen, Germany.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
authors.affiliation: Klinik und Poliklinik für Neurologie, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Haslinger
authors.affiliation: Institut für Humangenetik, Technische Universität München, 81675 Munich, Germany; Institut für Humangenetik, Helmholtz Zentrum München, 85764 Munich, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: Institut für Neurogenomik, Helmholtz Zentrum München, 85764 Munich, Germany; Klinik und Poliklinik für Neurologie, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany; Institut für Humangenetik, Technische Universität München, 81675 Munich, Germany; Munich Cluster for Systems Neurology, SyNergy, 81377 Munich, Germany. Electronic address: winkelmann@lrz.tu-muenchen.de.
authors.forename: Juliane
authors.initials: J
authors.lastname: Winkelmann
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001483:Base Sequence; D002648:Child; D020821:Dystonic Disorders / Q000235:genetics*; D005260:Female; D057895:Haploinsufficiency / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D008297:Male; D010375:Pedigree; D055815:Young Adult
chemical_list: D011495:Histone-Lysine N-Methyltransferase; C000619080:KMT2B protein, human; D008239:Lysine