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

被引：175

作者：

Meyer, Esther ^{[1
]}

Carss, Keren J. ^{[2
,3
]}

Rankin, Julia ^{[4
]}

Nichols, John M. E. ^{[5
,6
]}

Grozeva, Detelina ^{[7
]}

Joseph, Agnel P. ^{[8
]}

Mencacci, Niccolo E. ^{[9
]}

Papandreou, Apostolos ^{[10
,29
]}

Ng, Joanne ^{[1
,10
]}

Barra, Serena ^{[1
]}

Ngoh, Adeline ^{[1
,10
]}

Ben-Pazi, Hilla ^{[11
]}

Willemsen, Michel A. ^{[12
]}

Arkadir, David ^{[13
,14
]}

Barnicoat, Angela ^{[15
]}

Bergman, Hagai ^{[16
]}

Bhate, Sanjay ^{[10
]}

Boys, Amber ^{[17
]}

Darin, Niklas ^{[18
]}

Foulds, Nicola ^{[19
]}

Gutowski, Nicholas ^{[20
]}

Hills, Alison ^{[21
]}

Houlden, Henry ^{[9
]}

Hurst, Jane A. ^{[15
]}

Israe, Zvi ^{[22
]}

Kaminska, Margaret ^{[23
]}

Limousin, Patricia ^{[24
]}

Lumsden, Daniel ^{[23
]}

Mckee, Shane ^{[25
]}

Misra, Shibalik ^{[26
,27
]}

Mohammed, Shekeeb S. ^{[26
,27
]}

Nakou, Vasiliki ^{[23
]}

Nicolai, Joost ^{[28
]}

Nilsson, Magnus ^{[29
,30
]}

Pall, Hardev ^{[31
]}

Peall, Kathryn J. ^{[32
]}

Peters, Gregory B. ^{[33
]}

Prabhakar, Prab ^{[10
]}

Reuter, Miriam S. ^{[34
]}

Rump, Patrick ^{[35
]}

Sege, Reeval ^{[36
,37
,38
]}

Sinnema, Margje ^{[39
,40
]}

Smith, Martin ^{[41
]}

Turnpenny, Peter ^{[4
]}

White, Susan M. ^{[17
,42
]}

Wieczorek, Dagmar ^{[43
,44
]}

Wiethoff, Sarah ^{[9
]}

Wilson, Brian T. ^{[15
]}

Winter, Gidon ^{[11
]}

Wragg, Christopher ^{[21
]}

机构：

[1] UCL Inst Child Hlth, London, England

[2] Univ Cambridge, NHS Blood & Transplant Ctr, Dept Hematol, Cambridge, England

[3] Cambridge Univ Hosp, NIHR BioResource Rare Dis, Cambridge Biomed Campus, Cambridge, England

[4] Royal Devon & Exeter NHS Fdn Trust, Clin Genet, Exeter, Devon, England

[5] UCL, MRC Lab Mol Cell Biol, London, England

[6] UCL, Dept Cell & Dev Biol, London, England

[7] Univ Cambridge, Cambridge Inst Med Res, Dept Med Genet, Cambridge, England

[8] Univ London, Birkbeck Coll, Dept Biol Sci, Inst Struct & Mol Biol,Crystallog, London, England

[9] UCL Inst Neurol, Dept Mol Neurosci, London, England

[10] Great Ormond St Hosp Sick Children, Dept Neurol, London, England

[11] Shaare Zedek Mem Hosp, Pediatr Neurol & Dev, Jerusalem, Israel

[12] Radboud Univ Nijmegen Med Ctr, Donders Ctr Brain Cognit & Behav, Dept Paediat Neurol, Nijmegen, Netherlands

[13] Hadassah Med Ctr, Dept Neurol, Jerusalem, Israel

[14] Hebrew Univ Jerusalem, Jerusalem, Israel

[15] Great Ormond St Hosp Sick Children, Dept Clin Genet, London, England

[16] Hebrew Univ Jerusalem, Hadassah Med Ctr, Dept Neurobiol & Neurosurg, Jerusalem, Israel

[17] Murdoch Childrens Res Inst, Victoria Clin Genet Serv, Parkville, Vic, Australia

[18] Univ Gothenburg, Sahlgrenska Univ Hosp, Inst Clin Sci, Dept Pediat, Gothenburg, Sweden

[19] Southampton Gen Hosp, Dept Clin Genet, Southampton, Hants, England

[20] Royal Devon & Exeter NHS Fdn Trust, Dept Neurol, Exeter, Devon, England

[21] Southmead Hosp, Bristol Genet Lab, Pathol Sci, Bristol, Avon, England

[22] Hadassah Univ Hosp, Funct & Restorat Neurosurg, Jerusalem, Israel

[23] Guys & St Thomas NHS Fdn Trust, Evelina Childrens Hosp, Complex Motor Disorders Serv, London, England

[24] Natl Hosp Neurol & Neurosurg, Sobell Dept, London, England

[25] Belfast City Hosp, Northern Ireland Reg Genet Serv, Belfast, Antrim, North Ireland

[26] Univ Sydney, Child & Adolescent Hlth, Sydney, NSW, Australia

[27] Univ Sydney, Childrens Hosp Westmead, Inst Neurosci & Muscle Res, Sydney, NSW, Australia

[28] Maastricht Univ, Med Ctr, Dept Neurol, Maastricht, Netherlands

[29] Pitea Hosp, Dept Pediat, Umea, Sweden

[30] Umea Univ Hosp, Umea, Sweden

[31] Univ Birmingham, Coll Med & Dent Studies, Birmingham, W Midlands, England

[32] Cardiff Univ, Inst Psychol Med & Clin Neurosci, Neurosci & Mental Hlth Res Inst, Cardiff, S Glam, Wales

[33] Childrens Hosp Westmead, Dept Cytogenet, Westmead, NSW, Australia

[34] Univ Erlangen Nurnberg, Inst Human Genet, Erlangen, Germany

[35] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands

[36] Shaare Zedek Med Ctr, Inst Med Genet, Jerusalem, Israel

[37] Shaare Zedek Med Ctr, Pediat, Jerusalem, Israel

[38] Hebrew Univ Jerusalem, Sch Med, Jerusalem, Israel

[39] Maastricht Univ, Med Ctr, Dept Clin Genet, Maastricht, Netherlands

[40] Maastricht Univ, Med Ctr, Sch Oncol & Dev Biol GROW, Maastricht, Netherlands

[41] John Radcliffe Hosp, Dept Pediat Neurol, Oxford, England

[42] Univ Melbourne, Dept Pediat, Melbourne, Vic, Australia

[43] Univ Duisburg Essen, Inst Human Genet, Essen, Germany

[44] Heinrich Heine Univ, Fac Med, Inst Human Genet, Dusseldorf, Germany

[45] Natl Hosp Neurol & Neurosurg, Neurometab Unit, London, England

[46] NHS Fdn Trust, Great Ormond St Hosp, Clin Chem, London, England

[47] Great Ormond St Hosp Sick Children, North East Thames Reg Genet Serv, London, England

[48] Univ Barcelona, Hosp St Joan de Deu, Dept Child Neurol, Barcelona, Spain

[49] Hosp St Joan de Deu, Ctr Biomed Res Rare Dis CIBERER ISCIII, Barcelona, Spain

[50] US Natl Inst Hlth, Off Director, Common Fund, NIH Undiagnosed Dis Program, Bethesda, MD USA

来源：

NATURE GENETICS | 2017年 / 49卷 / 02期

基金：

英国惠康基金;

关键词：

PROTEIN STABILITY; NEURODEGENERATION; METHYLATION; DISORDERS;

D O I：

10.1038/ng.3740

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：223 / 237

页数：15

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