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

Meyer, E. and Carss, K.J and Rankin, J. and Nichols, J.M.E and Grozeva, D. and Joseph, A.P and Mencacci, N.E. and Papandreou, A. and Ng, J. and Barral, S. and Ngoh, A. and Ben-Pazi, H. and Willemsen, M.A. and Arkadir, D. and Barnicoat, A. and Bergman, H. and Bhate, S. and Boys, A. and Darin, N. and Foulds, N. and Gutowski, N. and Hills, A. and Houlden, H. and Hurst, J.A. and Israel, Z. and Kaminska, M. and Limousin, P. and Lumsden, D. and McKee, S. and Misra, S. and Mohammed, S.S. and Nakou, V. and Nicolai, J. and Nilsson, M. and Pall, H. and Peall, K.J. and Peters, G.B. and Prabhakar, P. and Reuter, M.S. and Rump, P. and Segel, R. and Sinnema, M. and Smith, M. and Turnpenny, P. and White, S.M. and Wieczorek, D. and Wiethoff, S. and Wilson, B.T. and Winter, G. and Wragg, C. and Pope, S. and Heales, S.J.H. and Morrogh, D. and Pittman, A. and Carr, L. J. and Perez-Dueñas, B. and Lin, J.-P. and Reis, A. and Gahl, W.A. and Toro, C. and Bhatia, K.P. and Wood, N.W. and Kamsteeg, E.-J. and Chong, W.K. and Gissen, P. and Topf, Maya and Dale, R.C. and Chubb, J.R. and Raymond, F.L. and Kurian, M.A. (2016) Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia. Nature Genetics 49 , pp. 223-237. ISSN 1061-4036.

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.

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