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, Barra 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, Israe 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 M, Rump P, Sege 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, Pittman A, Carr LJ, Perez-Duenas B, Lin JP, Reis A, Gahl WA, Toro C, Bhatia KP, Wood NW, Kamsteeg EJ, Chong WK, Gissen P, Topf M, Dale RC, Chubby JR, Raymond FL, Kurian MA (2016)

Publication Type: Journal article

Publication year: 2016

Journal

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.

Authors with CRIS profile

Involved external institutions

University College London (UCL) United Kingdom (GB) Cambridge University Hospital United Kingdom (GB) University of Sydney (USYD) Australia (AU) Great Ormond Street Hospital (GOSH) United Kingdom (GB) Radboud University Nijmegen Netherlands (NL) University College London Hospitals (UCLH) United Kingdom (GB) US National Institutes of Health (NIH) United States (USA) (US) Guy's and St Thomas' (NHS Foundation Trust) United Kingdom (GB) Universitat de Barcelona (UB) / University of Barcelona Spain (ES) Southmead Hospital United Kingdom (GB) Shaare Zedek Medical Center / מרכז רפואי שערי צדק‎‎, Israel (IL) Universität Duisburg-Essen (UDE) Germany (DE) Murdoch Childrens Research Institute Australia (AU) Royal Devon & Exeter NHS Foundation Trust United Kingdom (GB) John Radcliffe Hospital United Kingdom (GB) Maastricht University Netherlands (NL) University of Groningen / Rijksuniversiteit Groningen Netherlands (NL) Westmead Hospital Australia (AU) Cardiff University United Kingdom (GB) University of Birmingham United Kingdom (GB) Piteå hospital och asyl Sweden (SE) Belfast City Hospital / Ospidéal Chathair Bhéal Feirste United Kingdom (GB) Hadassah Medical Center / מרכז רפואי הדסה‎‎ Israel (IL) University Hospital Southampton NHS United Kingdom (GB) University of Gothenburg / Göteborgs universitet Sweden (SE) Hebrew University of Jerusalem Israel (IL) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) Netherlands (NL) University of Cambridge United Kingdom (GB)

How to cite

APA:

Meyer, E., Carss, K.J., Rankin, J., Nichols, J.M.E., Grozeva, D., Joseph, A.P.,... Kurian, M.A. (2016). Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia. Nature Genetics. https://dx.doi.org/10.1038/ng.3740

MLA:

Meyer, Esther, et al. "Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia." Nature Genetics (2016).

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