title: Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.
abstract: Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.
authors.affiliation: Molecular Neurosciences, Developmental Neurosciences, UCL Institute of Child Health, London, UK.
authors.forename: Esther
authors.initials: E
authors.lastname: Meyer
authors.affiliation: Department of Hematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge, UK.|NIHR BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Keren J
authors.initials: KJ
authors.lastname: Carss
authors.affiliation: Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
authors.forename: Julia
authors.initials: J
authors.lastname: Rankin
authors.affiliation: MRC Laboratory for Molecular Cell Biology and Department of Cell and Developmental Biology, University College London, London, UK.
authors.forename: John M E
authors.initials: JM
authors.lastname: Nichols
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
authors.forename: Detelina
authors.initials: D
authors.lastname: Grozeva
authors.affiliation: Institute of Structural and Molecular Biology, Crystallography/Department of Biological Sciences, Birkbeck College, University of London, London, UK.
authors.forename: Agnel P
authors.initials: AP
authors.lastname: Joseph
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Niccolo E
authors.identifier: http://orcid.org/0000-0003-3383-9665
authors.initials: NE
authors.lastname: Mencacci
authors.affiliation: Molecular Neurosciences, Developmental Neurosciences, UCL Institute of Child Health, London, UK.|Department of Neurology, Great Ormond Street Hospital, London, UK.
authors.forename: Apostolos
authors.identifier: http://orcid.org/0000-0001-5093-6075
authors.initials: A
authors.lastname: Papandreou
authors.affiliation: Molecular Neurosciences, Developmental Neurosciences, UCL Institute of Child Health, London, UK.|Department of Neurology, Great Ormond Street Hospital, London, UK.
authors.forename: Joanne
authors.initials: J
authors.lastname: Ng
authors.affiliation: Molecular Neurosciences, Developmental Neurosciences, UCL Institute of Child Health, London, UK.
authors.forename: Serena
authors.initials: S
authors.lastname: Barral
authors.affiliation: Molecular Neurosciences, Developmental Neurosciences, UCL Institute of Child Health, London, UK.|Department of Neurology, Great Ormond Street Hospital, London, UK.
authors.forename: Adeline
authors.initials: A
authors.lastname: Ngoh
authors.affiliation: Pediatric Neurology and Development, Shaare-Zedek Hospital, Jerusalem, Israel.
authors.forename: Hilla
authors.initials: H
authors.lastname: Ben-Pazi
authors.affiliation: Department of Paediatric Neurology, Donders Centre for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Michel A
authors.initials: MA
authors.lastname: Willemsen
authors.affiliation: Department of Neurology, Hadassah Medical Center and Hebrew University, Jerusalem, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Arkadir
authors.affiliation: Department of Clinical Genetics, Great Ormond Street Hospital, London, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Barnicoat
authors.affiliation: Department of Neurobiology and Neurosurgery, Hebrew University, Hadassah Medical Centre, Jerusalem, Israel.
authors.forename: Hagai
authors.identifier: http://orcid.org/0000-0002-2402-6673
authors.initials: H
authors.lastname: Bergman
authors.affiliation: Department of Neurology, Great Ormond Street Hospital, London, UK.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Bhate
authors.affiliation: Victoria Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
authors.forename: Amber
authors.initials: A
authors.lastname: Boys
authors.affiliation: Department of Pediatrics, Institute of Clinical Sciences, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Niklas
authors.initials: N
authors.lastname: Darin
authors.affiliation: Department of Clinical Genetics, Southampton General Hospital, Southampton, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Foulds
authors.affiliation: Department of Neurology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Gutowski
authors.affiliation: Bristol Genetics Laboratory, Pathology Sciences, Southmead Hospital, Bristol, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Hills
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.affiliation: Department of Clinical Genetics, Great Ormond Street Hospital, London, UK.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Hurst
authors.affiliation: Functional and Restorative Neurosurgery, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Zvi
authors.initials: Z
authors.lastname: Israel
authors.affiliation: Complex Motor Disorders Service, Evelina Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Margaret
authors.initials: M
authors.lastname: Kaminska
authors.affiliation: Sobell Department, National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Patricia
authors.initials: P
authors.lastname: Limousin
authors.affiliation: Complex Motor Disorders Service, Evelina Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lumsden
authors.affiliation: Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, UK.
authors.forename: Shane
authors.identifier: http://orcid.org/0000-0002-1772-0106
authors.initials: S
authors.lastname: McKee
authors.affiliation: Child and Adolescent Health, University of Sydney, Sydney, New South Wales, Australia.|Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Shibalik
authors.initials: S
authors.lastname: Misra
authors.affiliation: Child and Adolescent Health, University of Sydney, Sydney, New South Wales, Australia.|Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Shekeeb S
authors.identifier: http://orcid.org/0000-0003-1219-4781
authors.initials: SS
authors.lastname: Mohammed
authors.affiliation: Complex Motor Disorders Service, Evelina Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Nakou
authors.affiliation: Department of Neurology, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Nicolai
authors.affiliation: Department of Pediatrics, Piteå Hospital and Umeå University Hospital, Umeå, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Nilsson
authors.affiliation: College of Medicine and Dental Studies, University of Birmingham, Birmingham, UK.
authors.forename: Hardev
authors.initials: H
authors.lastname: Pall
authors.affiliation: Neuroscience and Mental Health Research Institute, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Peall
authors.affiliation: Department of Cytogenetics, Children's Hospital at Westmead, Westmead, New South Wales, Australia.
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Peters
authors.affiliation: Department of Neurology, Great Ormond Street Hospital, London, UK.
authors.forename: Prab
authors.initials: P
authors.lastname: Prabhakar
authors.affiliation: Institute of Human Genetics, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Miriam S
authors.initials: MS
authors.lastname: Reuter
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Patrick
authors.identifier: http://orcid.org/0000-0003-4059-0247
authors.initials: P
authors.lastname: Rump
authors.affiliation: Medical Genetics Institute and Pediatrics, Shaare-Zedek Medical Center and Hebrew University School of Medicine, Jerusalem, Israel.
authors.forename: Reeval
authors.initials: R
authors.lastname: Segel
authors.affiliation: Department of Clinical Genetics and School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Margje
authors.initials: M
authors.lastname: Sinnema
authors.affiliation: Department of Pediatric Neurology, John Radcliffe Hospital, Oxford, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Smith
authors.affiliation: Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Turnpenny
authors.affiliation: Victoria Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Victoria, Australia.|Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Susan M
authors.identifier: http://orcid.org/0000-0001-7611-634X
authors.initials: SM
authors.lastname: White
authors.affiliation: Institute of Human Genetics, University Duisburg-Essen, Essen, Germany.|Institute of Human Genetics, Heinrich Heine University, Medical Faculty, Düsseldorf, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wiethoff
authors.affiliation: Department of Clinical Genetics, Great Ormond Street Hospital, London, UK.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Wilson
authors.affiliation: Pediatric Neurology and Development, Shaare-Zedek Hospital, Jerusalem, Israel.
authors.forename: Gidon
authors.initials: G
authors.lastname: Winter
authors.affiliation: Bristol Genetics Laboratory, Pathology Sciences, Southmead Hospital, Bristol, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Wragg
authors.affiliation: Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Pope
authors.affiliation: Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK.|Clinical Chemistry, Great Ormond Street Hospital, NHS Foundation Trust, London, UK.
authors.forename: Simon J H
authors.initials: SJ
authors.lastname: Heales
authors.affiliation: North East Thames Regional Genetics Service, Great Ormond Street Hospital, London, UK.
authors.forename: Deborah
authors.initials: D
authors.lastname: Morrogh
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Pittman
authors.affiliation: Department of Neurology, Great Ormond Street Hospital, London, UK.
authors.forename: Lucinda J
authors.initials: LJ
authors.lastname: Carr
authors.affiliation: Department of Child Neurology, Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain.|Centre for Biomedical Research in Rare Diseases (CIBERER-ISCIII), Hospital Sant Joan de Déu, Barcelona, Spain.
authors.forename: Belen
authors.initials: B
authors.lastname: Perez-Dueñas
authors.affiliation: Complex Motor Disorders Service, Evelina Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Lin
authors.affiliation: Institute of Human Genetics, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Andre
authors.identifier: http://orcid.org/0000-0002-6301-6363
authors.initials: A
authors.lastname: Reis
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Camilo
authors.initials: C
authors.lastname: Toro
authors.affiliation: Sobell Department, National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Kailash P
authors.initials: KP
authors.lastname: Bhatia
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Erik-Jan
authors.initials: EJ
authors.lastname: Kamsteeg
authors.affiliation: Department of Radiology, Great Ormond Street Hospital, London, UK.
authors.forename: Wui K
authors.initials: WK
authors.lastname: Chong
authors.affiliation: MRC Laboratory for Molecular Cell Biology and Department of Cell and Developmental Biology, University College London, London, UK.
authors.forename: Paul
authors.identifier: http://orcid.org/0000-0002-9712-6122
authors.initials: P
authors.lastname: Gissen
authors.affiliation: Institute of Structural and Molecular Biology, Crystallography/Department of Biological Sciences, Birkbeck College, University of London, London, UK.
authors.forename: Maya
authors.initials: M
authors.lastname: Topf
authors.affiliation: Child and Adolescent Health, University of Sydney, Sydney, New South Wales, Australia.|Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Russell C
authors.initials: RC
authors.lastname: Dale
authors.affiliation: MRC Laboratory for Molecular Cell Biology and Department of Cell and Developmental Biology, University College London, London, UK.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Chubb
authors.affiliation: NIHR BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, UK.|Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
authors.forename: F Lucy
authors.initials: FL
authors.lastname: Raymond
authors.affiliation: Molecular Neurosciences, Developmental Neurosciences, UCL Institute of Child Health, London, UK.|Department of Neurology, Great Ormond Street Hospital, London, UK.
authors.forename: Manju A
authors.initials: MA
authors.lastname: Kurian
mesh_terms: D000293:Adolescent; D004268:DNA-Binding Proteins / Q000235:genetics; D004421:Dystonia / Q000235:genetics*; D005260:Female; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006657:Histones / Q000235:genetics; D006801:Humans; D008239:Lysine / Q000235:genetics; D008297:Male; D008745:Methylation; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D009687:Nuclear Proteins; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C000619080:KMT2B protein, human; D008239:Lysine