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

Esther Meyer, Keren J. Carss, Julia Rankin, John M. E. Nichols, Detelina Grozeva, Agnel P. Joseph, Niccolo E. Mencacci, Apostolos Papandreou, Joanne Ng, Serena Barra, Adeline Ngoh, Hilla Ben-Pazi, Michel A. Willemsen, David Arkadir, Angela Barnicoat, Hagai Bergman, Sanjay Bhate, Amber Boys, Niklas Darin, Nicola FouldsNicholas Gutowski, Alison Hills, Henry Houlden, Jane A. Hurst, Zvi Israe, Margaret Kaminska, Patricia Limousin, Daniel Lumsden, Shane Mckee, Shibalik Misra, Shekeeb S. Mohammed, Vasiliki Nakou, Joost Nicolai, Magnus Nilsson, Hardev Pall, Kathryn J. Peall, Gregory B. Peters, Prab Prabhakar, Miriam S. Reuter, Patrick Rump, Reeval Sege, Margje Sinnema, Martin Smith, Peter Turnpenny, Susan M. White, Dagmar Wieczorek, Sarah Wiethoff, Brian T. Wilson, Gidon Winter, Christopher Wragg, UK10K Consortium, Deciphering Dev Disorders Study, NIHR BioResource Rare, Manju Kurian*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

125 Citations (Web of Science)

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.

Original languageEnglish
Pages (from-to)223-237
Number of pages15
JournalNature Genetics
Volume49
Issue number2
DOIs
Publication statusPublished - Feb 2017

Keywords

  • BRAIN IRON ACCUMULATION
  • PROTEIN STABILITY
  • KABUKI SYNDROME
  • METHYLATION
  • DISORDERS
  • NEURODEGENERATION
  • MECHANISMS
  • VARIANTS
  • LEUKEMIA
  • UPDATE

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