학술논문
Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia
Document Type
Report
Author
Meyer, Esther; Carss, Keren J; Rankin, Julia; Nichols, John M E; Grozeva, Detelina; Joseph, Agnel P; Mencacci, Niccolo E; Papandreou, Apostolos; Ng, Joanne; Barral, Serena; Ngoh, Adeline; Ben-Pazi, Hilla; Willemsen, Michel A; Arkadir, David; Barnicoat, Angela; Bergman, Hagai; Bhate, Sanjay; Boys, Amber; Darin, Niklas; Foulds, Nicola; Gutowski, Nicholas; Hills, Alison; Houlden, Henry; Hurst, Jane A; Israel, Zvi; Kaminska, Margaret; Limousin, Patricia; Lumsden, Daniel; McKee, Shane; Misra, Shibalik; Mohammed, Shekeeb S; Nakou, Vasiliki; Nicolai, Joost; Nilsson, Magnus; Pall, Hardev; Peall, Kathryn J; Peters, Gregory B; Prabhakar, Prab; Reuter, Miriam S; Rump, Patrick; Segel, Reeval; Sinnema, Margje; Smith, Martin; Turnpenny, Peter; White, Susan M; Wieczorek, Dagmar; Wiethoff, Sarah; Wilson, Brian T; Winter, Gidon; Wragg, Christopher; Pope, Simon; Heales, Simon J H; Morrogh, Deborah; Pittman, Alan; Carr, Lucinda J; Perez-Dueñas, Belen; Lin, Jean-Pierre; Reis, Andre; Gahl, William A; Toro, Camilo; Bhatia, Kailash P; Wood, Nicholas W; Kamsteeg, Erik-Jan; Chong, Wui K; Gissen, Paul; Topf, Maya; Dale, Russell C; Chubb, Jonathan R; Raymond, F Lucy; Kurian, Manju A
Source
Nature Genetics. February 2017, Vol. 49 Issue 2, p223, 15 p.
Subject
Language
English
ISSN
1061-4036
Abstract
Author(s): Esther Meyer [1]; Keren J Carss [2, 3]; Julia Rankin [4]; John M E Nichols [5]; Detelina Grozeva [6]; Agnel P Joseph [7]; Niccolo E Mencacci [8]; Apostolos Papandreou [...]
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.
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.