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

Ashley L. Lennox; Mariah L. Hoye; Ruiji Jiang; Bethany L. Johnson-Kerner; Lindsey A. Suit; Srivats Venkataramanan; Charles J. Sheehan; Fernando C. Alsina; Brieana Fregeau; Kimberly A. Aldinger; Ching Moey; Iryna Lobach; Alexandra Afenjar; Dusica Babovic-Vuksanovic; Stéphane Bézieau; Patrick R. Blackburn; Jens Bunt; Lydie Burglen; Philippe M. Campeau; Perrine Charles; Brian H.Y. Chung; Benjamin Cogné; Cynthia Curry; Maria Daniela D'Agostino; Nataliya Di Donato; Laurence Faivre; Delphine Héron; A. Micheil Innes; Bertrand Isidor; Boris Keren; Amy Kimball; Eric W. Klee; Paul Kuentz; Sébastien Küry; Dominique Martin-Coignard; Ghayda Mirzaa; Cyril Mignot; Noriko Miyake; Naomichi Matsumoto; Atsushi Fujita; Caroline Nava; Mathilde Nizon; Diana Rodriguez; Lot Snijders Blok; Christel Thauvin-Robinet; Julien Thevenon; Marie Vincent; Alban Ziegler; William Dobyns; Linda J. Richards; A. James Barkovich; Stephen N. Floor; Debra L. Silver; Elliott H. Sherr

doi:10.1016/j.neuron.2020.01.042

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

Ashley L. Lennox, Mariah L. Hoye, Ruiji Jiang, Bethany L. Johnson-Kerner, Lindsey A. Suit, Srivats Venkataramanan, Charles J. Sheehan, Fernando C. Alsina, Brieana Fregeau, Kimberly A. Aldinger, Ching Moey, Iryna Lobach, Alexandra Afenjar, Dusica Babovic-Vuksanovic, Stéphane Bézieau, Patrick R. Blackburn, Jens Bunt, Lydie Burglen, Philippe M. Campeau, Perrine CharlesBrian H.Y. Chung, Benjamin Cogné, Cynthia Curry, Maria Daniela D'Agostino, Nataliya Di Donato, Laurence Faivre, Delphine Héron, A. Micheil Innes, Bertrand Isidor, Boris Keren, Amy Kimball, Eric W. Klee, Paul Kuentz, Sébastien Küry, Dominique Martin-Coignard, Ghayda Mirzaa, Cyril Mignot, Noriko Miyake, Naomichi Matsumoto, Atsushi Fujita, Caroline Nava, Mathilde Nizon, Diana Rodriguez, Lot Snijders Blok, Christel Thauvin-Robinet, Julien Thevenon, Marie Vincent, Alban Ziegler, William Dobyns, Linda J. Richards, A. James Barkovich, Stephen N. Floor, Debra L. Silver, Elliott H. Sherr

Bioscience/Biotechnology

Research output: Contribution to journal › Article › peer-review

64 Scopus citations

Abstract

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 highlight aberrant RNA metabolism in the pathogenesis of neurodevelopmental disease.

Original language	English (US)
Pages (from-to)	404-420.e8
Journal	Neuron
Volume	106
Issue number	3
DOIs	https://doi.org/10.1016/j.neuron.2020.01.042
State	Published - May 6 2020

Bibliographical note

Funding Information:
We thank the patients, their families, and referring physicians for their important contributions, and members of the Sherr and Silver labs for helpful discussions. This work was supported by the Holland-Trice Foundation , NIH R01NS083897 , R21NS098176 , and R01NS110388 (to D.L.S.); F31NS0933762 (to A.L.L.); Regeneration Next Initiative Postdoctoral Fellowship , NIH F32NS112566 (to M.L.H.), R25 (to B.L.J.-K.), 1R01NS058721 (to E.H.S., W.D., and L.J.R.), 5R01NS050375 (to W.D.); the DDX3X Foundation (to E.H.S.); National Health and Medical Research Council , Australia project grant GNT1126153 (to L.J.R. and E.H.S.); GNT1120615 Principal Research Fellowship from the NHMRC (to L.J.R.); UCSF Program for Breakthrough Biomedical Research , funded in part by the Sandler Foundation , California Tobacco-Related Disease Research Grants Program 27KT-0003 ( NIH DP2GM132932 ) (to S.N.F.); Dandy-Walker Alliance (to K.A.A. and W.D.); and the HUGODIMS Consortium RC14_0107 , funded in part by the French Ministry of Health and the Health Regional Agency from Poitou-Charentes, Frédérique Allaire from the Health Regional Agency of Poitou-Charentes (to S.K.).

Funding Information:
We thank the patients, their families, and referring physicians for their important contributions, and members of the Sherr and Silver labs for helpful discussions. This work was supported by the Holland-Trice Foundation, NIH R01NS083897, R21NS098176, and R01NS110388 (to D.L.S.); F31NS0933762 (to A.L.L.); Regeneration Next Initiative Postdoctoral Fellowship, NIH F32NS112566 (to M.L.H.), R25 (to B.L.J.-K.), 1R01NS058721 (to E.H.S. W.D. and L.J.R.), 5R01NS050375 (to W.D.); the DDX3X Foundation (to E.H.S.); National Health and Medical Research Council, Australia project grant GNT1126153 (to L.J.R. and E.H.S.); GNT1120615 Principal Research Fellowship from the NHMRC (to L.J.R.); UCSF Program for Breakthrough Biomedical Research, funded in part by the Sandler Foundation, California Tobacco-Related Disease Research Grants Program 27KT-0003 (NIH DP2GM132932) (to S.N.F.); Dandy-Walker Alliance (to K.A.A. and W.D.); and the HUGODIMS Consortium RC14_0107, funded in part by the French Ministry of Health and the Health Regional Agency from Poitou-Charentes, Fr?d?rique Allaire from the Health Regional Agency of Poitou-Charentes (to S.K.). A.L.L. R.J. L.J.R. D.L.S. and E.H.S. conceived and designed the study. A.L.L. M.L.H. R.J. B.L.J.-K. S.V. S.N.F. E.H.S. and D.L.S. wrote the manuscript. L.J.R. W.D. A.J.B. and B.L.J.-K. contributed to clinical study design and human imaging analysis. Data were generated by B.L.J.-K. L.A.S. and E.H.S. (Figures 1 and 2; Table 1), A.J.B. and E.H.S. with assistance from B.L.J.-K. (Figure 2), A.L.L. and C.M. with guidance from J.B. and D.L.S. (Figures 3 and S2), A.L.L. and M.L.H. with assistance from C.J.S. F.C.A. and D.L.S. (Figures 3, 4, 6, S3, S4, S5, and S6), R.J. with guidance from S.N.F. (Figure 5), S.V. (Figures 7A?7C), M.L.H. (Figure 7D), and I.L. L.A.S. and B.L.J.-K. (Figure S1; Tables 1 and S1). Patient recruitment, L.A.S. B.F. K.A.A. A.A. D.B.-.V. S.B. P.R.B. L.B. P.M.C. P.C. B.H.Y.C. B.C. C.C. M.D.D. N.D.D. L.F. D.H. A.M.I. B.I. B.K. A.K. E.W.K. P.K. S.K. D.M.-C. G.M. C.M. N. Miyake, N. Matsumoto, A.F. C.N. M.N. D.R. L.S.B. C.T.-R. J.T. M.V. A.Z. and E.H.S. All authors edited the manuscript. The authors declare no competing interests.

Publisher Copyright:
© 2020 Elsevier Inc.

Keywords

DDX3X
autism
corpus callosum
cortical development
helicase
intellectual disability
polymicrogyria
radial glial progenitor
stress granule
translation

UN SDGs

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

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10.1016/j.neuron.2020.01.042

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Lennox, A. L., Hoye, M. L., Jiang, R., Johnson-Kerner, B. L., Suit, L. A., Venkataramanan, S., Sheehan, C. J., Alsina, F. C., Fregeau, B., Aldinger, K. A., Moey, C., Lobach, I., Afenjar, A., Babovic-Vuksanovic, D., Bézieau, S., Blackburn, P. R., Bunt, J., Burglen, L., Campeau, P. M., ... Sherr, E. H. (2020). Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development. Neuron, 106(3), 404-420.e8. https://doi.org/10.1016/j.neuron.2020.01.042

Lennox, AL, Hoye, ML, Jiang, R, Johnson-Kerner, BL, Suit, LA, Venkataramanan, S, Sheehan, CJ, Alsina, FC, Fregeau, B, Aldinger, KA, Moey, C, Lobach, I, Afenjar, A, Babovic-Vuksanovic, D, Bézieau, S, Blackburn, PR, Bunt, J, Burglen, L, Campeau, PM, Charles, P, Chung, BHY, Cogné, B, Curry, C, D'Agostino, MD, Di Donato, N, Faivre, L, Héron, D, Innes, AM, Isidor, B, Keren, B, Kimball, A, Klee, EW, Kuentz, P, Küry, S, Martin-Coignard, D, Mirzaa, G, Mignot, C, Miyake, N, Matsumoto, N, Fujita, A, Nava, C, Nizon, M, Rodriguez, D, Blok, LS, Thauvin-Robinet, C, Thevenon, J, Vincent, M, Ziegler, A, Dobyns, W, Richards, LJ, Barkovich, AJ, Floor, SN, Silver, DL & Sherr, EH 2020, 'Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development', Neuron, vol. 106, no. 3, pp. 404-420.e8. https://doi.org/10.1016/j.neuron.2020.01.042

@article{5bab7d5cb7954263bff736229313f4ac,

title = "Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development",

abstract = "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 highlight aberrant RNA metabolism in the pathogenesis of neurodevelopmental disease.",

keywords = "DDX3X, autism, corpus callosum, cortical development, helicase, intellectual disability, polymicrogyria, radial glial progenitor, stress granule, translation",

author = "Lennox, {Ashley L.} and Hoye, {Mariah L.} and Ruiji Jiang and Johnson-Kerner, {Bethany L.} and Suit, {Lindsey A.} and Srivats Venkataramanan and Sheehan, {Charles J.} and Alsina, {Fernando C.} and Brieana Fregeau and Aldinger, {Kimberly A.} and Ching Moey and Iryna Lobach and Alexandra Afenjar and Dusica Babovic-Vuksanovic and St{\'e}phane B{\'e}zieau and Blackburn, {Patrick R.} and Jens Bunt and Lydie Burglen and Campeau, {Philippe M.} and Perrine Charles and Chung, {Brian H.Y.} and Benjamin Cogn{\'e} and Cynthia Curry and D'Agostino, {Maria Daniela} and {Di Donato}, Nataliya and Laurence Faivre and Delphine H{\'e}ron and Innes, {A. Micheil} and Bertrand Isidor and Boris Keren and Amy Kimball and Klee, {Eric W.} and Paul Kuentz and S{\'e}bastien K{\"u}ry and Dominique Martin-Coignard and Ghayda Mirzaa and Cyril Mignot and Noriko Miyake and Naomichi Matsumoto and Atsushi Fujita and Caroline Nava and Mathilde Nizon and Diana Rodriguez and Blok, {Lot Snijders} and Christel Thauvin-Robinet and Julien Thevenon and Marie Vincent and Alban Ziegler and William Dobyns and Richards, {Linda J.} and Barkovich, {A. James} and Floor, {Stephen N.} and Silver, {Debra L.} and Sherr, {Elliott H.}",

note = "Funding Information: We thank the patients, their families, and referring physicians for their important contributions, and members of the Sherr and Silver labs for helpful discussions. This work was supported by the Holland-Trice Foundation , NIH R01NS083897 , R21NS098176 , and R01NS110388 (to D.L.S.); F31NS0933762 (to A.L.L.); Regeneration Next Initiative Postdoctoral Fellowship , NIH F32NS112566 (to M.L.H.), R25 (to B.L.J.-K.), 1R01NS058721 (to E.H.S., W.D., and L.J.R.), 5R01NS050375 (to W.D.); the DDX3X Foundation (to E.H.S.); National Health and Medical Research Council , Australia project grant GNT1126153 (to L.J.R. and E.H.S.); GNT1120615 Principal Research Fellowship from the NHMRC (to L.J.R.); UCSF Program for Breakthrough Biomedical Research , funded in part by the Sandler Foundation , California Tobacco-Related Disease Research Grants Program 27KT-0003 ( NIH DP2GM132932 ) (to S.N.F.); Dandy-Walker Alliance (to K.A.A. and W.D.); and the HUGODIMS Consortium RC14_0107 , funded in part by the French Ministry of Health and the Health Regional Agency from Poitou-Charentes, Fr{\'e}d{\'e}rique Allaire from the Health Regional Agency of Poitou-Charentes (to S.K.). Funding Information: We thank the patients, their families, and referring physicians for their important contributions, and members of the Sherr and Silver labs for helpful discussions. This work was supported by the Holland-Trice Foundation, NIH R01NS083897, R21NS098176, and R01NS110388 (to D.L.S.); F31NS0933762 (to A.L.L.); Regeneration Next Initiative Postdoctoral Fellowship, NIH F32NS112566 (to M.L.H.), R25 (to B.L.J.-K.), 1R01NS058721 (to E.H.S. W.D. and L.J.R.), 5R01NS050375 (to W.D.); the DDX3X Foundation (to E.H.S.); National Health and Medical Research Council, Australia project grant GNT1126153 (to L.J.R. and E.H.S.); GNT1120615 Principal Research Fellowship from the NHMRC (to L.J.R.); UCSF Program for Breakthrough Biomedical Research, funded in part by the Sandler Foundation, California Tobacco-Related Disease Research Grants Program 27KT-0003 (NIH DP2GM132932) (to S.N.F.); Dandy-Walker Alliance (to K.A.A. and W.D.); and the HUGODIMS Consortium RC14_0107, funded in part by the French Ministry of Health and the Health Regional Agency from Poitou-Charentes, Fr?d?rique Allaire from the Health Regional Agency of Poitou-Charentes (to S.K.). A.L.L. R.J. L.J.R. D.L.S. and E.H.S. conceived and designed the study. A.L.L. M.L.H. R.J. B.L.J.-K. S.V. S.N.F. E.H.S. and D.L.S. wrote the manuscript. L.J.R. W.D. A.J.B. and B.L.J.-K. contributed to clinical study design and human imaging analysis. Data were generated by B.L.J.-K. L.A.S. and E.H.S. (Figures 1 and 2; Table 1), A.J.B. and E.H.S. with assistance from B.L.J.-K. (Figure 2), A.L.L. and C.M. with guidance from J.B. and D.L.S. (Figures 3 and S2), A.L.L. and M.L.H. with assistance from C.J.S. F.C.A. and D.L.S. (Figures 3, 4, 6, S3, S4, S5, and S6), R.J. with guidance from S.N.F. (Figure 5), S.V. (Figures 7A?7C), M.L.H. (Figure 7D), and I.L. L.A.S. and B.L.J.-K. (Figure S1; Tables 1 and S1). Patient recruitment, L.A.S. B.F. K.A.A. A.A. D.B.-.V. S.B. P.R.B. L.B. P.M.C. P.C. B.H.Y.C. B.C. C.C. M.D.D. N.D.D. L.F. D.H. A.M.I. B.I. B.K. A.K. E.W.K. P.K. S.K. D.M.-C. G.M. C.M. N. Miyake, N. Matsumoto, A.F. C.N. M.N. D.R. L.S.B. C.T.-R. J.T. M.V. A.Z. and E.H.S. All authors edited the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = may,

day = "6",

doi = "10.1016/j.neuron.2020.01.042",

language = "English (US)",

volume = "106",

pages = "404--420.e8",

journal = "Neuron",

issn = "0896-6273",

publisher = "Cell Press",

number = "3",

}

TY - JOUR

T1 - Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development

AU - Lennox, Ashley L.

AU - Hoye, Mariah L.

AU - Jiang, Ruiji

AU - Johnson-Kerner, Bethany L.

AU - Suit, Lindsey A.

AU - Venkataramanan, Srivats

AU - Sheehan, Charles J.

AU - Alsina, Fernando C.

AU - Fregeau, Brieana

AU - Aldinger, Kimberly A.

AU - Moey, Ching

AU - Lobach, Iryna

AU - Afenjar, Alexandra

AU - Babovic-Vuksanovic, Dusica

AU - Bézieau, Stéphane

AU - Blackburn, Patrick R.

AU - Bunt, Jens

AU - Burglen, Lydie

AU - Campeau, Philippe M.

AU - Charles, Perrine

AU - Chung, Brian H.Y.

AU - Cogné, Benjamin

AU - Curry, Cynthia

AU - D'Agostino, Maria Daniela

AU - Di Donato, Nataliya

AU - Faivre, Laurence

AU - Héron, Delphine

AU - Innes, A. Micheil

AU - Isidor, Bertrand

AU - Keren, Boris

AU - Kimball, Amy

AU - Klee, Eric W.

AU - Kuentz, Paul

AU - Küry, Sébastien

AU - Martin-Coignard, Dominique

AU - Mirzaa, Ghayda

AU - Mignot, Cyril

AU - Miyake, Noriko

AU - Matsumoto, Naomichi

AU - Fujita, Atsushi

AU - Nava, Caroline

AU - Nizon, Mathilde

AU - Rodriguez, Diana

AU - Blok, Lot Snijders

AU - Thauvin-Robinet, Christel

AU - Thevenon, Julien

AU - Vincent, Marie

AU - Ziegler, Alban

AU - Dobyns, William

AU - Richards, Linda J.

AU - Barkovich, A. James

AU - Floor, Stephen N.

AU - Silver, Debra L.

AU - Sherr, Elliott H.

N1 - Funding Information: We thank the patients, their families, and referring physicians for their important contributions, and members of the Sherr and Silver labs for helpful discussions. This work was supported by the Holland-Trice Foundation , NIH R01NS083897 , R21NS098176 , and R01NS110388 (to D.L.S.); F31NS0933762 (to A.L.L.); Regeneration Next Initiative Postdoctoral Fellowship , NIH F32NS112566 (to M.L.H.), R25 (to B.L.J.-K.), 1R01NS058721 (to E.H.S., W.D., and L.J.R.), 5R01NS050375 (to W.D.); the DDX3X Foundation (to E.H.S.); National Health and Medical Research Council , Australia project grant GNT1126153 (to L.J.R. and E.H.S.); GNT1120615 Principal Research Fellowship from the NHMRC (to L.J.R.); UCSF Program for Breakthrough Biomedical Research , funded in part by the Sandler Foundation , California Tobacco-Related Disease Research Grants Program 27KT-0003 ( NIH DP2GM132932 ) (to S.N.F.); Dandy-Walker Alliance (to K.A.A. and W.D.); and the HUGODIMS Consortium RC14_0107 , funded in part by the French Ministry of Health and the Health Regional Agency from Poitou-Charentes, Frédérique Allaire from the Health Regional Agency of Poitou-Charentes (to S.K.). Funding Information: We thank the patients, their families, and referring physicians for their important contributions, and members of the Sherr and Silver labs for helpful discussions. This work was supported by the Holland-Trice Foundation, NIH R01NS083897, R21NS098176, and R01NS110388 (to D.L.S.); F31NS0933762 (to A.L.L.); Regeneration Next Initiative Postdoctoral Fellowship, NIH F32NS112566 (to M.L.H.), R25 (to B.L.J.-K.), 1R01NS058721 (to E.H.S. W.D. and L.J.R.), 5R01NS050375 (to W.D.); the DDX3X Foundation (to E.H.S.); National Health and Medical Research Council, Australia project grant GNT1126153 (to L.J.R. and E.H.S.); GNT1120615 Principal Research Fellowship from the NHMRC (to L.J.R.); UCSF Program for Breakthrough Biomedical Research, funded in part by the Sandler Foundation, California Tobacco-Related Disease Research Grants Program 27KT-0003 (NIH DP2GM132932) (to S.N.F.); Dandy-Walker Alliance (to K.A.A. and W.D.); and the HUGODIMS Consortium RC14_0107, funded in part by the French Ministry of Health and the Health Regional Agency from Poitou-Charentes, Fr?d?rique Allaire from the Health Regional Agency of Poitou-Charentes (to S.K.). A.L.L. R.J. L.J.R. D.L.S. and E.H.S. conceived and designed the study. A.L.L. M.L.H. R.J. B.L.J.-K. S.V. S.N.F. E.H.S. and D.L.S. wrote the manuscript. L.J.R. W.D. A.J.B. and B.L.J.-K. contributed to clinical study design and human imaging analysis. Data were generated by B.L.J.-K. L.A.S. and E.H.S. (Figures 1 and 2; Table 1), A.J.B. and E.H.S. with assistance from B.L.J.-K. (Figure 2), A.L.L. and C.M. with guidance from J.B. and D.L.S. (Figures 3 and S2), A.L.L. and M.L.H. with assistance from C.J.S. F.C.A. and D.L.S. (Figures 3, 4, 6, S3, S4, S5, and S6), R.J. with guidance from S.N.F. (Figure 5), S.V. (Figures 7A?7C), M.L.H. (Figure 7D), and I.L. L.A.S. and B.L.J.-K. (Figure S1; Tables 1 and S1). Patient recruitment, L.A.S. B.F. K.A.A. A.A. D.B.-.V. S.B. P.R.B. L.B. P.M.C. P.C. B.H.Y.C. B.C. C.C. M.D.D. N.D.D. L.F. D.H. A.M.I. B.I. B.K. A.K. E.W.K. P.K. S.K. D.M.-C. G.M. C.M. N. Miyake, N. Matsumoto, A.F. C.N. M.N. D.R. L.S.B. C.T.-R. J.T. M.V. A.Z. and E.H.S. All authors edited the manuscript. The authors declare no competing interests. Publisher Copyright: © 2020 Elsevier Inc.

PY - 2020/5/6

Y1 - 2020/5/6

N2 - 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 highlight aberrant RNA metabolism in the pathogenesis of neurodevelopmental disease.

AB - 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 highlight aberrant RNA metabolism in the pathogenesis of neurodevelopmental disease.

KW - DDX3X

KW - autism

KW - corpus callosum

KW - cortical development

KW - helicase

KW - intellectual disability

KW - polymicrogyria

KW - radial glial progenitor

KW - stress granule

KW - translation

UR - http://www.scopus.com/inward/record.url?scp=85084076443&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85084076443&partnerID=8YFLogxK

U2 - 10.1016/j.neuron.2020.01.042

DO - 10.1016/j.neuron.2020.01.042

M3 - Article

C2 - 32135084

AN - SCOPUS:85084076443

SN - 0896-6273

VL - 106

SP - 404-420.e8

JO - Neuron

JF - Neuron

IS - 3

ER -

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

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