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

Meyer, E. et al. (2016) Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia. Nature Genetics, 49(2), pp. 223-237. (doi: 10.1038/ng.3740) (PMID:27992417)

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.

• Item Type: Articles
• Additional Information: 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 PrusinerAbramsky 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, AMRGN2097. 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 http://decipher.sanger.ac.uk/ and via e-mail from [e-mail]. 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 http://www.ddduk.org/access.html 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.).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Tobias, Professor Edward
• Authors: Meyer, E., Carss, K. J., Rankin, J., Nichols, J. M.E., Grozeva, D., Joseph, A. P., Mencacci, N. E., Papandreou, A., Ng, J., Barral, S., Ngoh, A., Ben-Pazi, H., Willemsen, M. A., Arkadir, D., Barnicoat, A., Bergman, H., Bhate, S., Boys, A., Darin, N., Foulds, N., Gutowski, N., Hills, A., Houlden, H., Hurst, J. A., Israel, Z., Kaminska, M., Limousin, P., Lumsden, D., McKee, S., Misra, S., Mohammed, S. S., Nakou, V., Nicolai, J., Nilsson, M., Pall, H., Peall, K. J., Peters, G. B., Prabhakar, P., Reuter, M. S., Rump, P., Segel, R., Sinnema, M., Smith, M., Turnpenny, P., White, S. M., Wieczorek, D., Wiethoff, S., Wilson, B. T.., Winter, G., Wragg, C., Pope, S., Heales, S. J.H., Morrogh, D., Pittman, A., Disorders Deciphering Developmental, , Carr, L. J., Perez-Dueñas, B., Lin, J.-P., Reis, A., Gahl, W. A., Toro, C., Bhatia, K. P., Wood, N. W., Kamsteeg, E.-J., Chong, W. K., Gissen, P., Topf, M., Dale, R. C., Chubb, J. R., Raymond, F. L., and Kurian, M. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: Nature Genetics
• Publisher: Nature Research
• ISSN: 1061-4036
• ISSN (Online): 1546-1718
• Copyright Holders: Copyright © 2017 Nature America, Inc., part of Springer Nature
• First Published: First published in Nature Genetics 49(2):223-237
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher