De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder

Lessel, Davor; Schob, Claudia; Küry, Sébastien; Reijnders, Margot R.F.; Harel, Tamar; Eldomery, Mohammad K.; Coban‐Akdemir, Zeynep; Denecke, Jonas; Edvardson, Simon; Colin, Estelle; Stegmann, Alexander P.A.; Gerkes, Erica H.; Tessarech, Marine; Bonneau, Dominique; Barth, Magalie; Besnard, Thomas; Cogné, Benjamin; Revah‐Politi, Anya; Strom, Tim M.; Rosenfeld, Jill A.; Yang, Yaping; Posey, Jennifer E.; Immken, LaDonna; Oundjian, Nelly Jouayed; Helbig, Ingo; Meeks, Naomi; Zegar, Kelsey; Morton, Jenny; study, the DDD; Schieving, Jolanda; Claasen, Ana M.; Huentelman, Matthew J.; Narayanan, Vinodh; Ramsey, Keri; Brunner, Han G.; Elpeleg, Orly; Mercier, Sandra; Bézieau, Stéphane; Kubisch, Christian; Kleefstra, Tjitske; Kindler, Stefan; Lupski, James R.; Kreienkamp, Hans‐Jürgen

doi:10.1016/j.ajhg.2017.12.016

Cited by 24 publications

(43 citation statements)

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“…Similar to FUS, DDX3X missense mutations also induce RNA-protein aggregates, which only partially overlap with stress granule markers Our study is amongst the first to link aberrant RNA-protein granules to the pathogenesis of neurodevelopment, which to date have been primarily associated with the etiology of neurodegeneration. One notable exception is the finding that de novo mutations in the RNA helicase DHX30 induce stress granules and cause ID and developmental delay (Lessel et al, 2018). Indeed, RNA binding proteins, including RNA helicases, are highly expressed in the developing neocortex and many are essential for cortical development and associated with disrupted neurodevelopment (Lennox et al, 2018).…”

Section: Ddx3x Missense Mutations Severely Disrupt Rna Metabolismmentioning

confidence: 99%

PathogenicDDX3Xmutations impair RNA metabolism and neurogenesis during fetal cortical development

Lennox

Jiang

Suit

et al. 2018

Preprint

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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=78), 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 neuronal generation and migration. Severe DDX3X missense mutations profoundly disrupt RNA helicase activity and induce ectopic RNA-protein granules and aberrant translation in neural progenitors and neurons. Together, our study demonstrates novel mechanisms underlying DDX3X syndrome, and highlights roles for RNA-protein aggregates in the pathogenesis of neurodevelopmental disease.

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Section: Ddx3x Missense Mutations Severely Disrupt Rna Metabolismmentioning

confidence: 99%

PathogenicDDX3Xmutations impair RNA metabolism and neurogenesis during fetal cortical development

Lennox

Jiang

Suit

et al. 2018

Preprint

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“…Two members of the DExD/H-box RNA helicase family, DHX30 (MIM: 616423) and DDX3X (MIM: 300160), have had multiple different pathogenic variant alleles associated with neurodevelopmental disorders including developmental delay and intellectual disability (DD and/or ID), speech impairment, brain abnormalities, and gait perturbations. [8][9][10][11][12] Twelve unrelated individuals with sporadic neurodevelopmental disorder with severe motor impairment and absent language (NEDMIAL [MIM: 617804]) were each found to have de novo missense DHX30 variants, of which four variants were found to be recurrent and located within nucleotide-interacting motifs of the helicase core region. 8 To date, at least 75 individuals have been reported to have neurodevelopmental delay (MRX102 [MIM: 300958]) in association with DDX3X variants.…”

Section: Introductionmentioning

confidence: 99%

“…[8][9][10][11][12] Twelve unrelated individuals with sporadic neurodevelopmental disorder with severe motor impairment and absent language (NEDMIAL [MIM: 617804]) were each found to have de novo missense DHX30 variants, of which four variants were found to be recurrent and located within nucleotide-interacting motifs of the helicase core region. 8 To date, at least 75 individuals have been reported to have neurodevelopmental delay (MRX102 [MIM: 300958]) in association with DDX3X variants. [9][10][11][12][13] Curiously, a majority of affected individuals for this X-linked condition are female, although a handful of males who inherited a DDX3X variant from an unaffected mother have been described, suggesting gender-specific variant pathogenicity.…”

Section: Introductionmentioning

confidence: 99%

Paralog Studies Augment Gene Discovery: DDX and DHX Genes

Paine

Posey

Grochowski

et al. 2019

The American Journal of Human Genetics

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Members of a paralogous gene family in which variation in one gene is known to cause disease are eight times more likely to also be associated with human disease. Recent studies have elucidated DHX30 and DDX3X as genes for which pathogenic variant alleles are involved in neurodevelopmental disorders. We hypothesized that variants in paralogous genes encoding members of the DExD/ H-box RNA helicase superfamily might also underlie developmental delay and/or intellectual disability (DD and/or ID) disease phenotypes. Here we describe 15 unrelated individuals who have DD and/or ID, central nervous system (CNS) dysfunction, vertebral anomalies, and dysmorphic features and were found to have probably damaging variants in DExD/H-box RNA helicase genes. In addition, these individuals exhibit a variety of other tissue and organ system involvement including ocular, outer ear, hearing, cardiac, and kidney tissues. Five individuals with homozygous (one), compound-heterozygous (two), or de novo (two) missense variants in DHX37 were identified by exome sequencing. We identified ten total individuals with missense variants in three other DDX/DHX paralogs: DHX16 (four individuals), DDX54 (three individuals), and DHX34 (three individuals). Most identified variants are rare, predicted to be damaging, and occur at conserved amino acid residues. Taken together, these 15 individuals implicate the DExD/H-box helicases in both dominantly and recessively inherited neurodevelopmental phenotypes and highlight the potential for more than one disease mechanism underlying these disorders.

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“…Notably, DHX30 has been recently associated with translation regulation of human mRNAs; it has indeed been identified as a component of the mammalian ribo-interactome (Simsek et al, 2017). Moreover, specific mutations were shown to impair its RNA recognition or ATPase activity and, when overexpressed, led to stress granule formation and inhibition of global translation (Lessel et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

p53-induced apoptosis is specified by a translation program regulated by PCBP2 and DHX30

Rizzotto

Zaccara

Rossi

et al. 2019

Preprint

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Activation of p53 by the small molecule Nutlin can result in a combination of cell cycle arrest and apoptosis. The relative strength of these events is difficult to predict by classical gene expression analysis, leaving uncertainty as to the therapeutic benefits of Nutlin. Here, we report a new translational control mechanism shaping p53-dependent apoptosis. Using polysome profiling, we establish Nutlin-induced apoptosis to be associated with the enhanced translation of mRNAs carrying multiple copies of a newly identified 3'UTR CG-rich motif mediating p53-dependent death (CGPD-motif). We identified PCBP2 and DHX30 as CGPDmotif interactors. We found that in cells undergoing persistent cell cycle arrest in response to Nutlin, CGPD-motif mRNAs are repressed by the PCBP2-dependent binding of DHX30 to the motif. Thus, upon DHX30 depletion in these cells, the translation of CGPD-motif mRNAs is increased, and the response to Nutlin shifts towards apoptosis. Instead, DHX30 inducible overexpression in SJSA1 cells, that undergo Nutlin-induced apoptosis, leads to decreased translation of CGPD-motif mRNAs. Overall, this work establishes the role of PCBP2-DHX30 in controlling the translation of CGPD-motif mRNAs and thus provide a new mechanism to modulate the induction of p53-dependent apoptosis.

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De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder

Cited by 24 publications

References 0 publications

PathogenicDDX3Xmutations impair RNA metabolism and neurogenesis during fetal cortical development

PathogenicDDX3Xmutations impair RNA metabolism and neurogenesis during fetal cortical development

Paralog Studies Augment Gene Discovery: DDX and DHX Genes

p53-induced apoptosis is specified by a translation program regulated by PCBP2 and DHX30

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