Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development

被引：121

作者：

Lennox, Ashley L. ^{[1
]}

Hoye, Mariah L. ^{[1
]}

Jiang, Ruiji ^{[2
]}

Johnson-Kerner, Bethany L. ^{[2
]}

Suit, Lindsey A. ^{[2
]}

Venkataramanan, Srivats ^{[3
]}

Sheehan, Charles J. ^{[1
]}

Alsina, Fernando C. ^{[1
]}

Fregeau, Brieana ^{[2
]}

Aldinger, Kimberly A. ^{[4
]}

Moey, Ching ^{[5
]}

Lobach, Iryna ^{[6
]}

Afenjar, Alexandra ^{[7
,8
]}

Babovic-Vuksanovic, Dusica ^{[9
,10
,11
]}

Bezieau, Stephane ^{[12
,13
]}

Blackburn, Patrick R. ^{[9
,14
]}

Bunt, Jens ^{[5
]}

Burglen, Lydie ^{[7
,8
]}

Campeau, Philippe M. ^{[15
,16
]}

Charles, Perrine ^{[17
,18
]}

Chung, Brian H. Y. ^{[19
]}

Cogne, Benjamin ^{[12
,13
]}

Curry, Cynthia ^{[20
]}

D'Agostino, Maria Daniela ^{[21
,22
]}

Di Donato, Nataliya ^{[23
]}

Faivre, Laurence ^{[24
,25
]}

Heron, Delphine ^{[26
]}

Innes, A. Micheil ^{[27
]}

Isidor, Bertrand ^{[12
,13
]}

Keren, Boris ^{[26
]}

Kimball, Amy ^{[28
]}

Klee, Eric W. ^{[9
,10
,14
,29
]}

Kuentz, Paul ^{[30
]}

Kury, Sebastien ^{[12
,13
]}

Martin-Coignard, Dominique ^{[31
]}

Mirzaa, Ghayda ^{[4
,32
]}

Mignot, Cyril ^{[17
,18
]}

Miyake, Noriko ^{[33
]}

Matsumoto, Naomichi ^{[33
]}

Fujita, Atsushi ^{[33
]}

Nava, Caroline ^{[26
]}

Nizon, Mathilde ^{[12
,13
]}

Rodriguez, Diana ^{[34
,35
]}

Blok, Lot Snijders ^{[36
]}

Thauvin-Robinet, Christel ^{[25
,37
]}

Thevenon, Julien ^{[24
,25
]}

Vincent, Marie ^{[12
,13
]}

Ziegler, Alban ^{[38
]}

Dobyns, William ^{[4
,32
,39
]}

Richards, Linda J. ^{[5
,40
]}

机构：

[1] Duke Univ, Dept Mol Genet & Microbiol, Med Ctr, Durham, NC 27710 USA

[2] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA

[3] Univ Calif San Francisco, Dept Cell & Tissue Biol, San Francisco, CA 94158 USA

[4] Seattle Childrens Res Inst, Ctr Integrat Brain Res, Seattle, WA 98101 USA

[5] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia

[6] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94158 USA

[7] Sorbonne Univ, Hop Armand Trousseau, AP HP, Ctr Reference Malformat & Malad Congenitales Cerv, Paris 75012, France

[8] Sorbonne Univ, Hop Armand Trousseau, AP HP, Dept Genet & Embryol Med, Paris 75012, France

[9] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA

[10] Mayo Clin, Dept Clin Genom, Rochester, MN 55905 USA

[11] Mayo Clin, Dept Pediat & Adolescent Med, Rochester, MN 55905 USA

[12] CHU Nantes, Serv Genet Med, 9 Quai Moncousu, Nantes 44093 1, France

[13] Univ Nantes, Inst Thorax, INSERM, CNRS, Nantes 44000, France

[14] Mayo Clin, Ctr Individualized Med, Rochester, MN 55905 USA

[15] Univ Montreal, Dept Pediat, Montreal, PQ, Canada

[16] CHU St Justine, Montreal, PQ, Canada

[17] Sorbonne Univ, Grp Hosp Pitie Salpetriere, Ctr Reference Deficiences Intellectuelles Causes, Dept Genet, Paris, France

[18] Sorbonne Univ, Hop Trousseau, AP HP, Paris, France

[19] Univ Hong Kong, Li Ka Shing Fac Med, Dept Paediat & Adolescent Med, Hong Kong, Peoples R China

[20] Univ Calif San Francisco Fresno, Genet Med, Fresno, CA 93701 USA

[21] McGill Univ, Dept Specialized Med, Div Med Genet, Montreal, PQ, Canada

[22] McGill Univ, Dept Human Genet, Div Med Genet, Montreal, PQ, Canada

[23] Tech Univ Dresden, Inst Clin Genet, Dresden, Germany

[24] CHU Dijon, Ctr Reference Anomalies Dev & Syndromes Malformat, INSERM, UMR 1231,GAD, Dijon, France

[25] Univ Bourgogne, Dijon, France

[26] Grp Hosp Pitie Salpetriere, AP HP, Dept Genet, Paris, France

[27] Univ Calgary, Cumming Sch Med, Dept Med Genet, Calgary, AB, Canada

[28] Greater Baltimore Med Ctr, Harvey Inst Human Genet, Baltimore, MD USA

[29] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA

[30] Univ Bourgogne Franche Comte, Genet Anomalies Dev, UMR INSERM 1231, GAD, Dijon, France

[31] Ctr Hosp Mans, Serv Genet, Le Mans, France

[32] Univ Washington, Dept Pediat, Seattle, WA 98101 USA

[33] Yokohama City Univ, Dept Human Genet, Grad Sch Med, Yokohama, Kanagawa 2360004, Japan

[34] Sorbonne Univ, Hop Armand Trousseau, AP HP, Ctr Reference Neurogenet, Paris 75012, France

[35] Sorbonne Univ, Hop Armand Trousseau, AP HP, Serv Neurol Pediat, Paris 75012, France

[36] Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, Nijmegen 6500 HB, Netherlands

[37] CHU Dijon, Ctr Reference Deficience Intellectuelle, INSERM UMR 1231, GAD, Dijon, France

[38] CHU Angers, Serv Genet, Angers, France

[39] Univ Washington, Dept Neurol, Seattle, WA 98101 USA

[40] Univ Queensland, Sch Biomed Sci, Brisbane, Qld 4072, Australia

[41] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94158 USA

[42] Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA

[43] Duke Univ, Dept Cell Biol, Med Ctr, Durham, NC 27710 USA

[44] Duke Univ, Dept Neurobiol, Med Ctr, Durham, NC 27710 USA

[45] Duke Univ, Duke Inst Brain Sci, Durham, NC 27710 USA

[46] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94158 USA

[47] Univ Calif San Francisco, Weill Inst Neurosci, San Francisco, CA 94158 USA

来源：

NEURON | 2020年 / 106卷 / 03期

基金：

澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;

关键词：

HELICASE DDX3; GENE-EXPRESSION; INTELLECTUAL DISABILITY; COMPLEX DETERMINES; CORPUS-CALLOSUM; COMMON-CAUSE; PROTEIN; TRANSLATION; SPECTRUM; INACTIVATION;

D O I：

10.1016/j.neuron.2020.01.042

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

De novo germline mutations in the RNA helicase DDX3X account for 1%-3% of unexplained intellectual disability (ID) cases in females and are associated with autism, brain malformations, and epilepsy. Yet, the developmental and molecular mechanisms by which DDX3X mutations impair brain function are unknown. Here, we use human and mouse genetics and cell biological and biochemical approaches to elucidate mechanisms by which pathogenic DDX3X variants disrupt brain development. We report the largest clinical cohort to date with DDX3X mutations (n = 107), demonstrating a striking correlation between recurrent dominant missense mutations, polymicrogyria, and the most severe clinical outcomes. We show that Ddx3x controls cortical development by regulating neuron generation. Severe DDX3X missense mutations profoundly disrupt RNA helicase activity, induce ectopic RNA-protein granules in neural progenitors and neurons, and impair translation. Together, these results uncover key mechanisms underlying DDX3X syndrome and high-light aberrant RNA metabolism in the pathogenesis of neurodevelopmental disease.

引用

页码：404 / +

页数：25

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