Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia

Esther Meyer¹, Keren J Carss^{2

3}, Julia Rankin⁴, John M E Nichols⁵, Detelina Grozeva⁶, Agnel P Joseph⁷, Niccolo E Mencacci⁸, Apostolos Papandreou^{1

9}, Joanne Ng^{1

9}, Serena Barral¹, Adeline Ngoh^{1

9}, Hilla Ben-Pazi¹⁰, Michel A Willemsen¹¹, David Arkadir¹², Angela Barnicoat¹³, Hagai Bergman¹⁴, Sanjay Bhate⁹, Amber Boys¹⁵, Niklas Darin¹⁶, Nicola Foulds¹⁷, Nicholas Gutowski¹⁸, Alison Hills¹⁹, Henry Houlden⁸, Jane A Hurst¹³, Zvi Israel²⁰, Margaret Kaminska²¹, Patricia Limousin²², Daniel Lumsden²¹, Shane McKee²³, Shibalik Misra^{24

25}, Shekeeb S Mohammed^{24

25}, Vasiliki Nakou²¹, Joost Nicolai²⁶, Magnus Nilsson²⁷, Hardev Pall²⁸, Kathryn J Peall²⁹, Gregory B Peters³⁰, Prab Prabhakar⁹, Miriam S Reuter³¹, Patrick Rump³², Reeval Segel³³, Margje Sinnema³⁴, Martin Smith³⁵, Peter Turnpenny⁴, Susan M White^{15

36}, Dagmar Wieczorek^{37

38}, Sarah Wiethoff⁸, Brian T Wilson¹³, Gidon Winter¹⁰, Christopher Wragg¹⁹, Simon Pope³⁹, Simon J H Heales^{39

40}, Deborah Morrogh⁴¹; UK10K Consortium; Deciphering Developmental Disorders Study; NIHR BioResource Rare Diseases Consortium; Alan Pittman⁸, Lucinda J Carr⁹, Belen Perez-Dueñas^{42

43}, Jean-Pierre Lin²¹, Andre Reis³¹, William A Gahl⁴⁴, Camilo Toro⁴⁴, Kailash P Bhatia²², Nicholas W Wood⁸, Erik-Jan Kamsteeg⁴⁵, Wui K Chong⁴⁶, Paul Gissen⁵, Maya Topf⁷, Russell C Dale^{24

25}, Jonathan R Chubb⁵, F Lucy Raymond^{3

6}, Manju A Kurian^{1

9}

Affiliations

¹ Molecular Neurosciences, Developmental Neurosciences, UCL Institute of Child Health, London, UK.
² Department of Hematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge, UK.
³ NIHR BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, UK.
⁴ Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
⁵ MRC Laboratory for Molecular Cell Biology and Department of Cell and Developmental Biology, University College London, London, UK.
⁶ Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
⁷ Institute of Structural and Molecular Biology, Crystallography/Department of Biological Sciences, Birkbeck College, University of London, London, UK.
⁸ Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
⁹ Department of Neurology, Great Ormond Street Hospital, London, UK.
¹⁰ Pediatric Neurology and Development, Shaare-Zedek Hospital, Jerusalem, Israel.
¹¹ Department of Paediatric Neurology, Donders Centre for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.
¹² Department of Neurology, Hadassah Medical Center and Hebrew University, Jerusalem, Israel.
¹³ Department of Clinical Genetics, Great Ormond Street Hospital, London, UK.
¹⁴ Department of Neurobiology and Neurosurgery, Hebrew University, Hadassah Medical Centre, Jerusalem, Israel.
¹⁵ Victoria Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
¹⁶ Department of Pediatrics, Institute of Clinical Sciences, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
¹⁷ Department of Clinical Genetics, Southampton General Hospital, Southampton, UK.
¹⁸ Department of Neurology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
¹⁹ Bristol Genetics Laboratory, Pathology Sciences, Southmead Hospital, Bristol, UK.
²⁰ Functional and Restorative Neurosurgery, Hadassah University Hospital, Jerusalem, Israel.
²¹ Complex Motor Disorders Service, Evelina Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK.
²² Sobell Department, National Hospital for Neurology and Neurosurgery, London, UK.
²³ Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, UK.
²⁴ Child and Adolescent Health, University of Sydney, Sydney, New South Wales, Australia.
²⁵ Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, University of Sydney, Sydney, New South Wales, Australia.
²⁶ Department of Neurology, Maastricht University Medical Center, Maastricht, the Netherlands.
²⁷ Department of Pediatrics, Piteå Hospital and Umeå University Hospital, Umeå, Sweden.
²⁸ College of Medicine and Dental Studies, University of Birmingham, Birmingham, UK.
²⁹ Neuroscience and Mental Health Research Institute, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
³⁰ Department of Cytogenetics, Children's Hospital at Westmead, Westmead, New South Wales, Australia.
³¹ Institute of Human Genetics, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.
³² Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
³³ Medical Genetics Institute and Pediatrics, Shaare-Zedek Medical Center and Hebrew University School of Medicine, Jerusalem, Israel.
³⁴ Department of Clinical Genetics and School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center, Maastricht, the Netherlands.
³⁵ Department of Pediatric Neurology, John Radcliffe Hospital, Oxford, UK.
³⁶ Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia.
³⁷ Institute of Human Genetics, University Duisburg-Essen, Essen, Germany.
³⁸ Institute of Human Genetics, Heinrich Heine University, Medical Faculty, Düsseldorf, Germany.
³⁹ Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK.
⁴⁰ Clinical Chemistry, Great Ormond Street Hospital, NHS Foundation Trust, London, UK.
⁴¹ North East Thames Regional Genetics Service, Great Ormond Street Hospital, London, UK.
⁴² Department of Child Neurology, Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain.
⁴³ Centre for Biomedical Research in Rare Diseases (CIBERER-ISCIII), Hospital Sant Joan de Déu, Barcelona, Spain.
⁴⁴ NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, US National Institutes of Health, Bethesda, Maryland, USA.
⁴⁵ Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
⁴⁶ Department of Radiology, Great Ormond Street Hospital, London, UK.

PMID: 27992417
DOI: 10.1038/ng.3740

Free article

Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia

Esther Meyer et al. Nat Genet. 2017 Feb.

Free article

. 2017 Feb;49(2):223-237.

doi: 10.1038/ng.3740. Epub 2016 Dec 19.

Authors

Affiliations

¹ Molecular Neurosciences, Developmental Neurosciences, UCL Institute of Child Health, London, UK.
² Department of Hematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge, UK.
³ NIHR BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, UK.
⁴ Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
⁵ MRC Laboratory for Molecular Cell Biology and Department of Cell and Developmental Biology, University College London, London, UK.
⁶ Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
⁷ Institute of Structural and Molecular Biology, Crystallography/Department of Biological Sciences, Birkbeck College, University of London, London, UK.
⁸ Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
⁹ Department of Neurology, Great Ormond Street Hospital, London, UK.
¹⁰ Pediatric Neurology and Development, Shaare-Zedek Hospital, Jerusalem, Israel.
¹¹ Department of Paediatric Neurology, Donders Centre for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.
¹² Department of Neurology, Hadassah Medical Center and Hebrew University, Jerusalem, Israel.
¹³ Department of Clinical Genetics, Great Ormond Street Hospital, London, UK.
¹⁴ Department of Neurobiology and Neurosurgery, Hebrew University, Hadassah Medical Centre, Jerusalem, Israel.
¹⁵ Victoria Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
¹⁶ Department of Pediatrics, Institute of Clinical Sciences, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
¹⁷ Department of Clinical Genetics, Southampton General Hospital, Southampton, UK.
¹⁸ Department of Neurology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
¹⁹ Bristol Genetics Laboratory, Pathology Sciences, Southmead Hospital, Bristol, UK.
²⁰ Functional and Restorative Neurosurgery, Hadassah University Hospital, Jerusalem, Israel.
²¹ Complex Motor Disorders Service, Evelina Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK.
²² Sobell Department, National Hospital for Neurology and Neurosurgery, London, UK.
²³ Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, UK.
²⁴ Child and Adolescent Health, University of Sydney, Sydney, New South Wales, Australia.
²⁵ Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, University of Sydney, Sydney, New South Wales, Australia.
²⁶ Department of Neurology, Maastricht University Medical Center, Maastricht, the Netherlands.
²⁷ Department of Pediatrics, Piteå Hospital and Umeå University Hospital, Umeå, Sweden.
²⁸ College of Medicine and Dental Studies, University of Birmingham, Birmingham, UK.
²⁹ Neuroscience and Mental Health Research Institute, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
³⁰ Department of Cytogenetics, Children's Hospital at Westmead, Westmead, New South Wales, Australia.
³¹ Institute of Human Genetics, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.
³² Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
³³ Medical Genetics Institute and Pediatrics, Shaare-Zedek Medical Center and Hebrew University School of Medicine, Jerusalem, Israel.
³⁴ Department of Clinical Genetics and School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center, Maastricht, the Netherlands.
³⁵ Department of Pediatric Neurology, John Radcliffe Hospital, Oxford, UK.
³⁶ Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia.
³⁷ Institute of Human Genetics, University Duisburg-Essen, Essen, Germany.
³⁸ Institute of Human Genetics, Heinrich Heine University, Medical Faculty, Düsseldorf, Germany.
³⁹ Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK.
⁴⁰ Clinical Chemistry, Great Ormond Street Hospital, NHS Foundation Trust, London, UK.
⁴¹ North East Thames Regional Genetics Service, Great Ormond Street Hospital, London, UK.
⁴² Department of Child Neurology, Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain.
⁴³ Centre for Biomedical Research in Rare Diseases (CIBERER-ISCIII), Hospital Sant Joan de Déu, Barcelona, Spain.
⁴⁴ NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, US National Institutes of Health, Bethesda, Maryland, USA.
⁴⁵ Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
⁴⁶ Department of Radiology, Great Ormond Street Hospital, London, UK.

PMID: 27992417
DOI: 10.1038/ng.3740

Erratum in

Corrigendum: Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.
Meyer E, Carss KJ, Rankin J, Nichols JME, Grozeva D, Joseph AP, Mencacci NE, Papandreou A, Ng J, Barral S, Ngoh A, Ben-Pazi H, Willemsen MA, Arkadir D, Barnicoat A, Bergman H, Bhate S, Boys A, Darin N, Foulds N, Gutowski N, Hills A, Houlden H, Hurst JA, Israel Z, Kaminska M, Limousin P, Lumsden D, McKee S, Misra S, Mohammed SS, Nakou V, Nicolai J, Nilsson M, Pall H, Peall KJ, Peters GB, Prabhakar P, Reuter MS, Rump P, Segel R, Sinnema M, Smith M, Turnpenny P, White SM, Wieczorek D, Wiethoff S, Wilson BT, Winter G, Wragg C, Pope S, Heales SJH, Morrogh D; UK10K Consortium; Deciphering Developmental Disorders Study; NIHR BioResource Rare Diseases Consortium; Pittman A, Carr LJ, Perez-Dueñas B, Lin JP, Reis A, Gahl WA, Toro C, Bhatia KP, Wood NW, Kamsteeg EJ, Chong WK, Gissen P, Topf M, Dale RC, Chubb JR, Raymond FL, Kurian MA. Meyer E, et al. Nat Genet. 2017 May 26;49(6):969. doi: 10.1038/ng0617-969b. Nat Genet. 2017. PMID: 28546572 No abstract available.

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.

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Comment in

Dystonia: opportunities to gain insights into underlying pathophysiological mechanisms.
Peall KJ, Robertson NP. Peall KJ, et al. J Neurol. 2017 Mar;264(3):616-618. doi: 10.1007/s00415-017-8411-5. J Neurol. 2017. PMID: 28188465 Free PMC article. No abstract available.
KMT2B: A new twist in dystonia genetics.
Balint B, Valente EM. Balint B, et al. Mov Disord. 2017 Apr;32(4):529. doi: 10.1002/mds.26957. Epub 2017 Feb 20. Mov Disord. 2017. PMID: 28218417 No abstract available.

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Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia

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Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia

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