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

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Title:	Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia
Author(s):	Meyer, E.; Carss, K.J.; Rankin, J.; Nichols, J.M.; 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.; Morrogh, D.; Pittman, A.; Carr, L.J.; Perez-Duenas, 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.; Kurian, M.A.
Publication year:	2017
Source:	Nature Genetics, vol. 49, iss. 2, (2017), pp. 223-237
ISSN:	1061-4036
DOI:	https://doi.org/10.1038/ng.3740
Publication type:	Article / Letter to editor
Please use this identifier to cite or link to this item : http://hdl.handle.net/2066/169757
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Subject:	Radboudumc 12: Sensory disorders DCMN: Donders Center for Medical Neuroscience Radboudumc 3: Disorders of movement DCMN: Donders Center for Medical Neuroscience
Organization:	Amalia Childrens Hospital Neurology Paediatrics Radboudumc Extern Human Genetics
Journal title:	Nature Genetics
Volume:	vol. 49
Issue:	iss. 2
Page start:	p. 223
Page end:	p. 237
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.