De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation

被引：28

作者：

Basilicata, M. Felicia ^{[1
]}

Bruel, Ange-Line ^{[2
,3
]}

Semplicio, Giuseppe ^{[1
]}

Valsecchi, Claudia Isabelle Keller ^{[1
]}

Aktas, Tugce ^{[1
]}

Duffourd, Yannis ^{[2
,3
]}

Rumpf, Tobias ^{[1
]}

Morton, Jenny ^{[4
,5
]}

Bache, Iben ^{[6
,7
]}

Szymanski, Witold G. ^{[1
]}

Gilissen, Christian ^{[8
]}

Vanakker, Olivier ^{[9
]}

Ounap, Katrin ^{[10
,11
]}

Mittler, Gerhard ^{[1
]}

Van Der Burgt, Ineke ^{[8
]}

El Chehadeh, Salima ^{[2
,3
,12
]}

Cho, Megan T. ^{[13
]}

Pfundt, Rolph ^{[8
]}

Tan, Tiong Yang ^{[14
]}

Kirchhoff, Maria ^{[6
]}

Menten, Bjorn ^{[9
]}

Vergult, Sarah ^{[9
]}

Lindstrom, Kristin ^{[15
]}

Reis, Andre ^{[16
]}

Johnson, Diana S. ^{[17
]}

Fryer, Alan ^{[18
]}

McKay, Victoria ^{[18
]}

Fisher, Richard B. ^{[19
]}

Thauvin-Robinet, Christel ^{[2
,3
]}

Francis, David ^{[20
]}

Roscioli, Tony ^{[21
,22
,23
]}

Pajusalu, Sander ^{[10
,11
]}

Radtke, Kelly ^{[24
]}

Ganesh, Jaya ^{[25
,26
]}

Brunner, Han G. ^{[8
,27
,28
]}

Wilson, Meredith ^{[29
,30
]}

Faivre, Laurence ^{[2
,3
]}

Kalscheuer, Vera M. ^{[31
]}

Thevenon, Julien ^{[2
,3
,32
]}

Akhtar, Asifa ^{[1
]}

机构：

[1] Max Planck Inst Immunobiol & Epigenet, Freiburg, Germany

[2] Univ Bourgogne Franche Comte, Genet Dev Disorders, Inserm UMR GAD 1231, Dijon, France

[3] Univ Bourgogne Franche Comte, Ctr Reference Malad Rares Anomalies Dev & Syndrom, Dijon, France

[4] Birmingham Womens Hosp NHS Fdn Trust, West Midlands Reg Clin Genet Serv, Birmingham, W Midlands, England

[5] Birmingham Womens Hosp NHS Fdn Trust, Birmingham Hlth Partners, Birmingham, W Midlands, England

[6] Copenhagen Univ Hosp, Rigshosp, Dept Clin Genet, Copenhagen, Denmark

[7] Univ Copenhagen, Wilhelm Johannsen Ctr Funct Genome Res, Dept Cellular & Mol Med, Copenhagen, Denmark

[8] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Dept Human Genet, Med Ctr, Nijmegen, Netherlands

[9] Ghent Univ Hosp, Ctr Med Genet, Ghent, Belgium

[10] Univ Tartu, Tartu Univ Hosp, Dept Clin Genet, United Labs, Tartu, Estonia

[11] Univ Tartu, Inst Clin Med, Tartu, Estonia

[12] Hop Hautepierre, Serv Genet Med, Strasbourg, France

[13] GeneDx, Gaithersburg, MD USA

[14] Univ Melbourne, Royal Childrens Hosp, Murdoch Childrens Res Inst, Victorian Clin Genet Serv,Dept Paediat, Parkville, Vic, Australia

[15] Phoenix Childrens Hosp, Div Genet & Metab, Phoenix, AZ USA

[16] Friedrich Alexander Univ Erlangen Nurnberg, Inst Human Genet, Erlangen, Germany

[17] Sheffield Childrens NHS Fdn Trust, Clin Genet Serv, Sheffield, S Yorkshire, England

[18] Liverpool Womens NHS Fdn Trust, Dept Clin Genet, Liverpool, Merseyside, England

[19] James Cook Univ Hosp, Northern Genet Serv, Teesside Genet Unit, Middlesbrough, Cleveland, England

[20] Royal Childrens Hosp, Murdoch Childrens Res Inst, Victorian Clin Genet Serv, Cytogenet Lab, Victoria, Australia

[21] Neurosci Res Australia, Sydney, NSW, Australia

[22] Univ New South Wales, Prince Wales Clin Sch, Sydney, NSW, Australia

[23] Sydney Childrens Hosp, Dept Med Genet, Sydney, NSW, Australia

[24] Ambry Genet, Dept Clin Genom, Aliso Viejo, CA USA

[25] Rowan Univ, Div Genet, Cooper Univ Hosp, Camden, NJ USA

[26] Rowan Univ, Cooper Med Sch, Camden, NJ USA

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

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

[29] Univ Sydney, Childrens Hosp Westmead, Dept Clin Genet, Discipline Genet Med, Sydney, NSW, Australia

[30] Univ Sydney, Childrens Hosp Westmead, Dept Clin Genet, Discipline Child & Adolescent Hlth, Sydney, NSW, Australia

[31] Max Planck Inst Mol Genet, Res Grp Dev & Dis, Berlin, Germany

[32] Univ Grenoble Alpes, Inst Adv Biosci, U1209, CHU Grenoble,INSERM,CNRS UMR 5309, Grenoble, France

来源：

NATURE GENETICS | 2018年 / 50卷 / 10期

基金：

英国惠康基金;

关键词：

DOSAGE COMPENSATION; MOF; DEACETYLASE; CHROMOSOME; ACETYLTRANSFERASE; COMPLEX; DISORDERS; TRANSCRIPTION; ARCHITECTURE; INHERITANCE;

D O I：

10.1038/s41588-018-0220-y

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

The etiological spectrum of ultra-rare developmental disorders remains to be fully defined. Chromatin regulatory mechanisms maintain cellular identity and function, where misregulation may lead to developmental defects. Here, we report pathogenic variations in MSL3, which encodes a member of the chromatin-associated male-specific lethal (MSL) complex responsible for bulk histone H4 lysine 16 acetylation (H4K16ac) in flies and mammals. These variants cause an X-linked syndrome affecting both sexes. Clinical features of the syndrome include global developmental delay, progressive gait disturbance, and recognizable facial dysmorphism. MSL3 mutations affect MSL complex assembly and activity, accompanied by a pronounced loss of H4K16ac levels in vivo. Patient-derived cells display global transcriptome alterations of pathways involved in morphogenesis and cell migration. Finally, we use histone deacetylase inhibitors to rebalance acetylation levels, alleviating some of the molecular and cellular phenotypes of patient cells. Taken together, we characterize a syndrome that allowed us to decipher the developmental importance of MSL3 in humans.

引用

页码：1442 / +

页数：13

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