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 Foulds; Nicholas 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

doi:10.1038/ng.3740

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 journal › Article › Academic › peer-review

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 language	English
Pages (from-to)	223-237
Number of pages	15
Journal	Nature Genetics
Volume	49
Issue number	2
DOIs	https://doi.org/10.1038/ng.3740
Publication status	Published - Feb 2017

Keywords

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

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10.1038/ng.3740

Cite this

Meyer, E., Carss, K. J., Rankin, J., Nichols, J. M. E., Grozeva, D., Joseph, A. P., Mencacci, N. E., Papandreou, A., Ng, J., Barra, S., Ngoh, A., Ben-Pazi, H., Willemsen, M. A., Arkadir, D., Barnicoat, A., Bergman, H., Bhate, S., Boys, A., Darin, N., ... Kurian, M. (2017). Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia. Nature Genetics, 49(2), 223-237. https://doi.org/10.1038/ng.3740

@article{82a5d0562c574a139a07655cbdeb4c13,

title = "Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia",

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.",

keywords = "BRAIN IRON ACCUMULATION, PROTEIN STABILITY, KABUKI SYNDROME, METHYLATION, DISORDERS, NEURODEGENERATION, MECHANISMS, VARIANTS, LEUKEMIA, UPDATE",

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

year = "2017",

month = feb,

doi = "10.1038/ng.3740",

language = "English",

volume = "49",

pages = "223--237",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "2",

}

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, MS, Rump, P, Sege, R, Sinnema, M, Smith, M, Turnpenny, P, White, SM, Wieczorek, D, Wiethoff, S, Wilson, BT, Winter, G, Wragg, C, UK10K Consortium, Deciphering Dev Disorders Study, NIHR BioResource Rare & Kurian, M 2017, 'Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia', Nature Genetics, vol. 49, no. 2, pp. 223-237. https://doi.org/10.1038/ng.3740

TY - JOUR

T1 - Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia

AU - Meyer, Esther

AU - Carss, Keren J.

AU - Rankin, Julia

AU - Nichols, John M. E.

AU - Grozeva, Detelina

AU - Joseph, Agnel P.

AU - Mencacci, Niccolo E.

AU - Papandreou, Apostolos

AU - Ng, Joanne

AU - Barra, Serena

AU - Ngoh, Adeline

AU - Ben-Pazi, Hilla

AU - Willemsen, Michel A.

AU - Arkadir, David

AU - Barnicoat, Angela

AU - Bergman, Hagai

AU - Bhate, Sanjay

AU - Boys, Amber

AU - Darin, Niklas

AU - Foulds, Nicola

AU - Gutowski, Nicholas

AU - Hills, Alison

AU - Houlden, Henry

AU - Hurst, Jane A.

AU - Israe, Zvi

AU - Kaminska, Margaret

AU - Limousin, Patricia

AU - Lumsden, Daniel

AU - Mckee, Shane

AU - Misra, Shibalik

AU - Mohammed, Shekeeb S.

AU - Nakou, Vasiliki

AU - Nicolai, Joost

AU - Nilsson, Magnus

AU - Pall, Hardev

AU - Peall, Kathryn J.

AU - Peters, Gregory B.

AU - Prabhakar, Prab

AU - Reuter, Miriam S.

AU - Rump, Patrick

AU - Sege, Reeval

AU - Sinnema, Margje

AU - Smith, Martin

AU - Turnpenny, Peter

AU - White, Susan M.

AU - Wieczorek, Dagmar

AU - Wiethoff, Sarah

AU - Wilson, Brian T.

AU - Winter, Gidon

AU - Wragg, Christopher

AU - UK10K Consortium

AU - Deciphering Dev Disorders Study

AU - NIHR BioResource Rare

AU - Kurian, Manju

PY - 2017/2

Y1 - 2017/2

N2 - 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.

AB - 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.

KW - BRAIN IRON ACCUMULATION

KW - PROTEIN STABILITY

KW - KABUKI SYNDROME

KW - METHYLATION

KW - DISORDERS

KW - NEURODEGENERATION

KW - MECHANISMS

KW - VARIANTS

KW - LEUKEMIA

KW - UPDATE

U2 - 10.1038/ng.3740

DO - 10.1038/ng.3740

M3 - Article

C2 - 27992417

SN - 1061-4036

VL - 49

SP - 223

EP - 237

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -