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

  • Nat Genet. 2017 Feb;49(2):223-237. doi: 10.1038/ng.3740.
Esther Meyer  1 ,  Keren J Carss  2  3 ,  Julia Rankin  4 ,  John M E Nichols  5 ,  Detelina Grozeva  6 ,  Agnel P Joseph  7 ,  Niccolo E Mencacci  8 ,  Apostolos Papandreou  1  9 ,  Joanne Ng  1  9 ,  Serena Barral  1 ,  Adeline Ngoh  1  9 ,  Hilla Ben-Pazi  10 ,  Michel A Willemsen  11 ,  David Arkadir  12 ,  Angela Barnicoat  13 ,  Hagai Bergman  14 ,  Sanjay Bhate  9 ,  Amber Boys  15 ,  Niklas Darin  16 ,  Nicola Foulds  17 ,  Nicholas Gutowski  18 ,  Alison Hills  19 ,  Henry Houlden  8 ,  Jane A Hurst  13 ,  Zvi Israel  20 ,  Margaret Kaminska  21 ,  Patricia Limousin  22 ,  Daniel Lumsden  21 ,  Shane McKee  23 ,  Shibalik Misra  24  25 ,  Shekeeb S Mohammed  24  25 ,  Vasiliki Nakou  21 ,  Joost Nicolai  26 ,  Magnus Nilsson  27 ,  Hardev Pall  28 ,  Kathryn J Peall  29 ,  Gregory B Peters  30 ,  Prab Prabhakar  9 ,  Miriam S Reuter  31 ,  Patrick Rump  32 ,  Reeval Segel  33 ,  Margje Sinnema  34 ,  Martin Smith  35 ,  Peter Turnpenny  4 ,  Susan M White  15  36 ,  Dagmar Wieczorek  37  38 ,  Sarah Wiethoff  8 ,  Brian T Wilson  13 ,  Gidon Winter  10 ,  Christopher Wragg  19 ,  Simon Pope  39 ,  Simon J H Heales  39  40 ,  Deborah Morrogh  41 ,  UK10K Consortium ,  Deciphering Developmental Disorders Study ,  NIHR BioResource Rare Diseases Consortium ,  Alan Pittman  8 ,  Lucinda J Carr  9 ,  Belen Perez-Dueñas  42  43 ,  Jean-Pierre Lin  21 ,  Andre Reis  31 ,  William A Gahl  44 ,  Camilo Toro  44 ,  Kailash P Bhatia  22 ,  Nicholas W Wood  8 ,  Erik-Jan Kamsteeg  45 ,  Wui K Chong  46 ,  Paul Gissen  5 ,  Maya Topf  7 ,  Russell C Dale  24  25 ,  Jonathan R Chubb  5 ,  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
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.