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

Research output: Contribution to journalArticlepeer-review

11 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 languageEnglish (US)
Pages (from-to)404-420.e8
JournalNeuron
Volume106
Issue number3
DOIs
StatePublished - May 6 2020
Externally publishedYes

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

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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