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 Barral; 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 Israel; 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 Segel; Margje Sinnema; Martin Smith; Peter Turnpenny; Susan M. White; Dagmar Wieczorek; Sarah Wiethoff; Brian T. Wilson; Gidon Winter; Christopher Wragg; Simon Pope; Simon J.H. Heales; Deborah Morrogh; Alan Pittman; Lucinda J. Carr; Belen Perez-Duenãs; Andre Reis; William A. Gahl; Camilo Toro; Kailash P. Bhatia; Nicholas W. Wood; Erik Jan Kamsteeg; Wui K. Chong; Paul Gissen; Maya Topf; Russell C. Dale; Jonathan R. Chubb; F. Lucy Raymond; Manju A. Kurian

doi:https://doi.org/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 Barral, 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 Israel, 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 Segel, Margje Sinnema, Martin Smith, Peter Turnpenny, Susan M. White, Dagmar Wieczorek, Sarah Wiethoff, Brian T. Wilson, Gidon Winter, Christopher Wragg, Simon Pope, Simon J.H. Heales, Deborah Morrogh, Alan Pittman, Lucinda J. Carr, Belen Perez-Duenãs, Andre Reis, William A. Gahl, Camilo Toro, Kailash P. Bhatia, Nicholas W. Wood, Erik Jan Kamsteeg, Wui K. Chong, Paul Gissen, Maya Topf, Russell C. Dale, Jonathan R. Chubb, F. Lucy Raymond, Manju A. Kurian

Edmond & Lily Safra Center for Brain Sciences

The Hebrew University of Jerusalem

Research output: Contribution to journal › Article › 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	American 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
State	Published - 31 Jan 2017

All Science Journal Classification (ASJC) codes

Genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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https://doi.org/10.1038/ng.3740

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Meyer, E., Carss, K. J., Rankin, J., Nichols, J. M. E., Grozeva, D., Joseph, A. P., Mencacci, N. E., Papandreou, A., Ng, J., Barral, S., Ngoh, A., Ben-Pazi, H., Willemsen, M. A., Arkadir, D., Barnicoat, A., Bergman, H., Bhate, S., Boys, A., Darin, N., ... Kurian, M. A. (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{857738711b6c4e5d91f31c9136ce4e9b,

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.",

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 Barral 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 Israel 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 Segel 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 Simon Pope and Heales, {Simon J.H.} and Deborah Morrogh and Alan Pittman and Carr, {Lucinda J.} and Belen Perez-Duen{\~a}s and Andre Reis and Gahl, {William A.} and Camilo Toro and Bhatia, {Kailash P.} and Wood, {Nicholas W.} and Kamsteeg, {Erik Jan} and Chong, {Wui K.} and Paul Gissen and Maya Topf and Dale, {Russell C.} and Chubb, {Jonathan R.} and Raymond, {F. Lucy} and Kurian, {Manju A.}",

note = "Publisher Copyright: {\textcopyright} 2017 Nature America, Inc., part of Springer Nature.",

year = "2017",

month = jan,

day = "31",

doi = "https://doi.org/10.1038/ng.3740",

language = "American English",

volume = "49",

pages = "223--237",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "2",

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Meyer, E, Carss, KJ, Rankin, J, Nichols, JME, Grozeva, D, Joseph, AP, Mencacci, NE, Papandreou, A, Ng, J, Barral, 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, Israel, 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, Segel, 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-Duenãs, B, Reis, A, Gahl, WA, Toro, C, Bhatia, KP, Wood, NW, Kamsteeg, EJ, Chong, WK, Gissen, P, Topf, M, Dale, RC, Chubb, JR, Raymond, FL & Kurian, MA 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 - Barral, 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 - Israel, 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 - Segel, 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 - Pope, Simon

AU - Heales, Simon J.H.

AU - Morrogh, Deborah

AU - Pittman, Alan

AU - Carr, Lucinda J.

AU - Perez-Duenãs, Belen

AU - Reis, Andre

AU - Gahl, William A.

AU - Toro, Camilo

AU - Bhatia, Kailash P.

AU - Wood, Nicholas W.

AU - Kamsteeg, Erik Jan

AU - Chong, Wui K.

AU - Gissen, Paul

AU - Topf, Maya

AU - Dale, Russell C.

AU - Chubb, Jonathan R.

AU - Raymond, F. Lucy

AU - Kurian, Manju A.

PY - 2017/1/31

Y1 - 2017/1/31

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.

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U2 - https://doi.org/10.1038/ng.3740

DO - https://doi.org/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 -

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

Abstract

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UN SDGs

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