Article | Published:

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

Nature Genetics volume 49, pages 223237 (2017) | Download Citation

  • A Corrigendum to this article was published on 26 May 2017

This article has been updated


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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Change history

  • 20 April 2017

    Following publication of this article, the authors were asked to remove a clinical image and some video footage of one of the affected individuals. Although consent was obtained, in keeping with their ethical consent framework, the authors allow for withdrawal of consent and are carrying out the wishes of the research subjects under their consent process. This amendment has been made in the HTML and PDF versions of the article.



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We thank all our patients and their families for taking part in this study and encouraging international collaboration to seek out similar cases. Thanks are given to M. Ishida (GOS-ICH) for kindly providing the fetal cDNA, K. Tuschl (GOS-ICH) for kindly providing the human cDNA panel, L. Bassioni (Great Ormond Street Hospital, GOSH) for kindly selecting DaTSCAN images for the supplementary manuscript, M. Adams (National Hospital for Neurology and Neurosurgery, NHNN) for reviewing the imaging of the patients at NHNN and R. Meijer for helping with the sequencing analysis at the Department of Human Genetics (Nijmegen). We thank G. Moore (GOS-ICH) and P. Stanier (GOS-ICH) for proofreading the manuscript. Many thanks are given to A. Panahian-Jand (GOSH) for excellent administrative support. M.A.K. has a Wellcome Intermediate Clinical Fellowship (WT098524MA). E.M. and M.A.K. received funding from the Rosetrees Trust, the Great Ormond Street Hospital Children's Charity and the Gracious Heart Foundation. N.E.M. receives support from the UK Department of Health's NIHR Biomedical Research Centers funding streams. A. Papandreou has a joint Action Medical Research/British Paediatric Neurology Association Research Training Fellowship. J. Ng has an MRC Research Training Fellowship. A.N. has an Action Medical Research Training Fellowship. H.B.-P. has a DBS training travel grant from the Daniel Turnberg Trust Fund. H.H. is funded by the MRC and Wellcome Trust (Synaptopathies award). D.A. is supported by the Prusiner-Abramsky Award. H.P. has received grant support from the Dystonia Society (UK). K.J.P. has an Academy of Medical Sciences Clinical Starter Grant. B.P.-D. received funding from grants 20143130-La Marató de TV3 and PI15/00287-Ministerio Español de Economia y Competitividad. J.-P.L. has been supported by Guy's and St Thomas' Charity New Services and Innovation Grant G060708, the Dystonia Society (UK), grants 01/2011 and 07/2013 and an Action Medical Research, AMR-GN2097. This research was supported by the NIHR Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust, University College London and University of Cambridge and by funding from the NIHR for the BioResource for Rare Diseases (grant RG65966). This study makes use of data generated by the DECIPHER community. A full list of centers contributing to the generation of the data is available from and via e-mail from Funding for the project was provided by the Wellcome Trust for UK10K (WT091310) and the DDD study. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant HICF-1009-003); see for full acknowledgment. This work was supported in part by the Intramural Research Program of the National Human Genome Research Institute and the Common Fund, NIH Office of the Director. This work was supported in part by the German Ministry of Research and Education (grants 01GS08160 and 01GS08167; German Mental Retardation Network) as part of the National Genome Research Network to A.R. and D.W., and by the Deutsche Forschungsgemeinschaft (AB393/2-2) to A.R. Brain expression data were provided by the UK Human Brain Expression Consortium (UKBEC), which comprises John A. Hardy, Mina Ryten, Michael Weale, Daniah Trabzuni, Adaikalavan Ramasamy, Colin Smith and Robert Walker, affiliated with the UCL Institute of Neurology (J.A.H., M.R. and D.T.), King's College London (M.R., M.W. and A.R.) and the University of Edinburgh (C.S. and R.W.).

Author information

Author notes

    • Esther Meyer
    • , Keren J Carss
    • , Julia Rankin
    •  & John M E Nichols

    These authors contributed equally to this work.

    • F Lucy Raymond
    •  & Manju A Kurian

    These authors jointly directed this work.


  1. Molecular Neurosciences, Developmental Neurosciences, UCL Institute of Child Health, London, UK.

    • Esther Meyer
    • , Apostolos Papandreou
    • , Joanne Ng
    • , Serena Barral
    • , Adeline Ngoh
    •  & Manju A Kurian
  2. Department of Hematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge, UK.

    • Keren J Carss
  3. NIHR BioResource–Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, UK.

    • Keren J Carss
    •  & F Lucy Raymond
  4. Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.

    • Julia Rankin
    •  & Peter Turnpenny
  5. MRC Laboratory for Molecular Cell Biology and Department of Cell and Developmental Biology, University College London, London, UK.

    • John M E Nichols
    • , Paul Gissen
    •  & Jonathan R Chubb
  6. Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.

    • Detelina Grozeva
    •  & F Lucy Raymond
  7. Institute of Structural and Molecular Biology, Crystallography/Department of Biological Sciences, Birkbeck College, University of London, London, UK.

    • Agnel P Joseph
    •  & Maya Topf
  8. Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.

    • Niccolo E Mencacci
    • , Henry Houlden
    • , Sarah Wiethoff
    • , Alan Pittman
    •  & Nicholas W Wood
  9. Department of Neurology, Great Ormond Street Hospital, London, UK.

    • Apostolos Papandreou
    • , Joanne Ng
    • , Adeline Ngoh
    • , Sanjay Bhate
    • , Prab Prabhakar
    • , Lucinda J Carr
    •  & Manju A Kurian
  10. Pediatric Neurology and Development, Shaare-Zedek Hospital, Jerusalem, Israel.

    • Hilla Ben-Pazi
    •  & Gidon Winter
  11. Department of Paediatric Neurology, Donders Centre for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.

    • Michel A Willemsen
  12. Department of Neurology, Hadassah Medical Center and Hebrew University, Jerusalem, Israel.

    • David Arkadir
  13. Department of Clinical Genetics, Great Ormond Street Hospital, London, UK.

    • Angela Barnicoat
    • , Jane A Hurst
    •  & Brian T Wilson
  14. Department of Neurobiology and Neurosurgery, Hebrew University, Hadassah Medical Centre, Jerusalem, Israel.

    • Hagai Bergman
  15. Victoria Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Victoria, Australia.

    • Amber Boys
    •  & Susan M White
  16. Department of Pediatrics, Institute of Clinical Sciences, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.

    • Niklas Darin
  17. Department of Clinical Genetics, Southampton General Hospital, Southampton, UK.

    • Nicola Foulds
  18. Department of Neurology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.

    • Nicholas Gutowski
  19. Bristol Genetics Laboratory, Pathology Sciences, Southmead Hospital, Bristol, UK.

    • Alison Hills
    •  & Christopher Wragg
  20. Functional and Restorative Neurosurgery, Hadassah University Hospital, Jerusalem, Israel.

    • Zvi Israel
  21. Complex Motor Disorders Service, Evelina Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK.

    • Margaret Kaminska
    • , Daniel Lumsden
    • , Vasiliki Nakou
    •  & Jean-Pierre Lin
  22. Sobell Department, National Hospital for Neurology and Neurosurgery, London, UK.

    • Patricia Limousin
    •  & Kailash P Bhatia
  23. Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, UK.

    • Shane McKee
  24. Child and Adolescent Health, University of Sydney, Sydney, New South Wales, Australia.

    • Shibalik Misra
    • , Shekeeb S Mohammed
    •  & Russell C Dale
  25. Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, University of Sydney, Sydney, New South Wales, Australia.

    • Shibalik Misra
    • , Shekeeb S Mohammed
    •  & Russell C Dale
  26. Department of Neurology, Maastricht University Medical Center, Maastricht, the Netherlands.

    • Joost Nicolai
  27. Department of Pediatrics, Piteå Hospital and Umeå University Hospital, Umeå, Sweden.

    • Magnus Nilsson
  28. College of Medicine and Dental Studies, University of Birmingham, Birmingham, UK.

    • Hardev Pall
  29. Neuroscience and Mental Health Research Institute, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.

    • Kathryn J Peall
  30. Department of Cytogenetics, Children's Hospital at Westmead, Westmead, New South Wales, Australia.

    • Gregory B Peters
  31. Institute of Human Genetics, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.

    • Miriam S Reuter
    •  & Andre Reis
  32. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

    • Patrick Rump
  33. Medical Genetics Institute and Pediatrics, Shaare-Zedek Medical Center and Hebrew University School of Medicine, Jerusalem, Israel.

    • Reeval Segel
  34. Department of Clinical Genetics and School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center, Maastricht, the Netherlands.

    • Margje Sinnema
  35. Department of Pediatric Neurology, John Radcliffe Hospital, Oxford, UK.

    • Martin Smith
  36. Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia.

    • Susan M White
  37. Institute of Human Genetics, University Duisburg-Essen, Essen, Germany.

    • Dagmar Wieczorek
  38. Institute of Human Genetics, Heinrich Heine University, Medical Faculty, Düsseldorf, Germany.

    • Dagmar Wieczorek
  39. Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK.

    • Simon Pope
    •  & Simon J H Heales
  40. Clinical Chemistry, Great Ormond Street Hospital, NHS Foundation Trust, London, UK.

    • Simon J H Heales
  41. North East Thames Regional Genetics Service, Great Ormond Street Hospital, London, UK.

    • Deborah Morrogh
  42. Department of Child Neurology, Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain.

    • Belen Perez-Dueñas
  43. Centre for Biomedical Research in Rare Diseases (CIBERER-ISCIII), Hospital Sant Joan de Déu, Barcelona, Spain.

    • Belen Perez-Dueñas
  44. NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, US National Institutes of Health, Bethesda, Maryland, USA.

    • William A Gahl
    •  & Camilo Toro
  45. Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.

    • Erik-Jan Kamsteeg
  46. Department of Radiology, Great Ormond Street Hospital, London, UK.

    • Wui K Chong


  1. UK10K Consortium

    A list of members and affiliations appears in the Supplementary Note.

  2. Deciphering Developmental Disorders Study

    A list of members and affiliations appears in the Supplementary Note.

  3. NIHR BioResource Rare Diseases Consortium

    A list of members and affiliations appears in the Supplementary Note.


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E.M., K.J.C., J.M.E.N., J.R.C., F.L.R. and M.A.K. conceived and designed experiments. J.R., N.E.M., A. Papandreou, J. Ng, H.B.-P., M.A.W., D.A., A. Barnicoat, H.B., S. Bhate, N.D., N.F., N.G., A.H., H.H., J.A.H., Z.I., M.K., P.L., D.L., S. McKee, S. Misra, S.S.M., V.N., J. Nicolai, M.N., H.P., K.J.P., G.B.P., P.P., M.S.R., P.R., R.S., M. Sinnema, M. Smith, P.T., S.M.W., D.W., B.T.W., G.W., the UK10K Consortium, the DDD study, the NIHRBR-RD Consortium, L.J.C., B.P.-D., J.-P.L., A.R., W.A.G., C.T., K.P.B., N.W.W., E.-J.K., P.G., R.C.D., F.L.R. and M.A.K. ascertained patients and contributed clinical information, photographs, videos and neuroimaging studies. M.A.K. performed phenotypic characterization of all patients. W.K.C. and M.A.K. reviewed patient neuroimaging. A. Papandreou and M.A.K. edited patient videos. A. Boys, C.W. and D.M. undertook chromosomal microarray analysis. E.M., K.J.C., D.G., N.E.M., S.W., A. Pittman, the UK10K Consortium, the DDD Study, the NIHRBR-RD Consortium, A.R., W.A.G., C.T., E.-J.K. and M.A.K. carried out whole-exome and whole-genome sequencing analysis. E.M. and A.N. performed variant validation by direct Sanger sequencing. K.J.C. performed enrichment analysis (and corresponding statistical analysis). S.P. and S.J.H.H. analyzed CSF neurotransmitters. A.P.J. and M.T. undertook comparative homology modeling. J.M.E.N. and J.R.C. undertook the histone methylation assays (and corresponding statistical analysis) and cloning of the Set1 point substitution in Dictyostelium. S. Barral generated dopaminergic neurons, collected RNA and cDNA samples, and undertook qRT–PCR experiments. E.M. maintained fibroblast cultures, collected RNA, cDNA and protein samples, and performed fibroblast immunoblotting analysis (and corresponding statistical analysis) and CSF immunoblotting (and corresponding statistical analysis). J. Ng carried out CSF immunoblotting analysis. P.G. and F.L.R. contributed critical suggestions for experimental work. E.M. and M.A.K. wrote the manuscript. K.J.C., J.R., J.M.E.N., D.G., A.P.J., N.E.M., A.R., W.A.G., C.T., E.-J.K., W.K.C., M.T., J.R.C. and F.L.R. contributed written sections for the manuscript. M.A.K. oversaw the overall project. All authors critically reviewed manuscript.

Competing interests

H.P. has unrestricted support for educational activity from Medtronic.

Corresponding author

Correspondence to Manju A Kurian.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–14, Supplementary Tables 1–11 and Supplementary Note.


  1. 1.

    Supplementary Video 1

    Lower-limb dystonia and gait disturbance in patients with KMT2B variants.

  2. 2.

    Supplementary Video 2

    Upper-limb dystonia in patients with KMT2B variants.

  3. 3.

    Supplementary Video 3

    Progression to generalized dystonia in patients with KMT2B variants.

  4. 4.

    Supplementary Video 4

    Cranial, cervical and laryngeal features in patients with KMT2B variants.

  5. 5.

    Supplementary Video 5

    Motor overflow secondary to dystonia in patients with KMT2B variants.

  6. 6.

    Supplementary Video 6

    Dystonic crisis in a patient with a KMT2B mutation.

  7. 7.

    Supplementary Video 7

    Myoclonus dystonia in a patient with a KMT2B mutation

  8. 8.

    Supplementary Video 8

    Response to deep brain stimulation in patient 9.

  9. 9.

    Supplementary Video 9

    Response to deep brain stimulation in patient 17.

  10. 10.

    Supplementary Video 10

    Response to deep brain stimulation in patient 21.

  11. 11.

    Supplementary Video 11

    Response to deep brain stimulation in patient 22.

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