Developmental and Behavioral Phenotypes in a Mouse Model of DDX3X Syndrome

Boitnott, Andrea; Garcia‐Forn, Marta; Ung, Dévina C.; Niblo, Kristi; Mendonca, Danielle; Park, Yeaji; Flores, Michael; Maxwell, Sylvia; Ellegood, Jacob; Qiu, Lily R.; Grice, Dorothy E.; Lerch, Jason P.; Rašin, Mladen-Roko; Buxbaum, Joseph D.; Drapeau, Elodie; Rubeis, Silvia De

doi:10.1016/j.biopsych.2021.05.027

Cited by 30 publications

(15 citation statements)

References 63 publications

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“…The former class likely results in DDX3X haploinsufficiency and/or hypomorphic loss-of-function (LoF) ( Figure 1A ). Consistent with this, in female mice, Ddx3x germline haploinsufficiency impairs postnatal brain architecture and causes behavioral deficits phenocopying aspects of human DDX3X syndrome ( Boitnott et al, 2021 ). In addition, using transient CRISPR approaches we previously showed that acute Ddx3x depletion in a subset of cells perturbed progenitor and neuron number ( Lennox et al, 2020 ).…”

Section: Introductionmentioning

confidence: 58%

Aberrant cortical development is driven by impaired cell cycle and translational control in a DDX3X syndrome model

Hoye

Poff

Ejimogu

et al. 2022

eLife

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Mutations in the RNA helicase, DDX3X, are a leading cause of Intellectual Disability and present as DDX3X syndrome, a neurodevelopmental disorder associated with cortical malformations and autism. Yet, the cellular and molecular mechanisms by which DDX3X controls cortical development are largely unknown. Here, using a mouse model of Ddx3x loss-of-function we demonstrate that DDX3X directs translational and cell cycle control of neural progenitors, which underlies precise corticogenesis. First, we show brain development is sensitive to Ddx3x dosage; complete Ddx3x loss from neural progenitors causes microcephaly in females, whereas hemizygous males and heterozygous females show reduced neurogenesis without marked microcephaly. In addition, Ddx3x loss is sexually dimorphic, as its paralog, Ddx3y, compensates for Ddx3x in the developing male neocortex. Using live imaging of progenitors, we show that DDX3X promotes neuronal generation by regulating both cell cycle duration and neurogenic divisions. Finally, we use ribosome profiling in vivo to discover the repertoire of translated transcripts in neural progenitors, including those which are DDX3X-dependent and essential for neurogenesis. Our study reveals invaluable new insights into the etiology of DDX3X syndrome, implicating dysregulated progenitor cell cycle dynamics and translation as pathogenic mechanisms.

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Section: Introductionmentioning

confidence: 58%

Aberrant cortical development is driven by impaired cell cycle and translational control in a DDX3X syndrome model

Hoye

Poff

Ejimogu

et al. 2022

eLife

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“…1A). Consistent with this, in female mice, Ddx3x germline haploinsufficiency impairs postnatal brain architecture and causes behavioral deficits phenocopying aspects of human DDX3X syndrome (Boitnott et al 2021). In addition, using transient CRISPR approaches we previously showed that acute Ddx3x depletion in a subset of cells perturbed progenitor and neuron number (Lennox et al 2020).…”

Section: Introductionmentioning

confidence: 62%

“…New insights into Ddx3x dosage requirements and redundant roles of DDX3X and DDX3Y would not have been gained with germline LoF models, due to male lethality (Chen et al 2016a). A recent report assessed behavioral phenotypes of a germline mouse model of Ddx3x haploinsufficiency in females (Boitnott et al 2021). Consistent with our cHet phenotypes, these females were not microcephalic, but did have reduced Ctip2+ (layer V) neurons in the somatosensory cortex at P3, which persisted into adulthood.…”

Section: Discussionmentioning

confidence: 99%

Aberrant cortical development is driven by impaired cell cycle and translational control in aDDX3Xsyndrome model

Hoye

Poff

Ejimogu³

et al. 2022

Preprint

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Mutations in the RNA helicase, DDX3X, are a leading cause of Intellectual Disability and present as DDX3X syndrome, a neurodevelopmental disorder associated with cortical malformations and autism. Yet the cellular and molecular mechanisms by which DDX3X controls cortical development are largely unknown. Here, using a mouse model of Ddx3x loss-of-function we demonstrate that DDX3X directs translational and cell cycle control of neural progenitors, which underlies precise corticogenesis. First, we show brain development is highly sensitive to Ddx3x dosage; Complete Ddx3x loss from neural progenitors causes microcephaly in females, whereas hemizygous males and heterozygous females show reduced neurogenesis without marked microcephaly. In addition, Ddx3x loss is sexually dimorphic, as its paralog, Ddx3y, compensates for Ddx3x in the developing male neocortex. Using live imaging of progenitors, we show that DDX3X promotes neuronal generation by regulating both cell cycle duration and neurogenic divisions. Finally, we use ribosome profiling in vivo to discover the repertoire of translated transcripts in neural progenitors, including those which are DDX3X-dependent and essential for neurogenesis. Our study reveals invaluable new insights into the etiology of DDX3X syndrome, implicating dysregulated progenitor cell cycle dynamics and translation as pathogenic mechanisms.

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“…Dd3x neural stem cells knockout at embryonic day (E) 9.5 in mice hampered brain growth, accompanied by seizures and ataxia ( Patmore et al, 2020 ). Boitnott et al (2021) generated a Ddx3x haploinsufficient mouse (Ddx3x ± female) with construct validity for DDX3X loss-of-function mutations. The Ddx3x ± mice showed global development delay and evolved into behavioral anomalies in adulthood ( Boitnott et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“… Boitnott et al (2021) generated a Ddx3x haploinsufficient mouse (Ddx3x ± female) with construct validity for DDX3X loss-of-function mutations. The Ddx3x ± mice showed global development delay and evolved into behavioral anomalies in adulthood ( Boitnott et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Expansion of Clinical and Genetic Spectrum of DDX3X Neurodevelopmental Disorder in 23 Chinese Patients

Dai

Yang

Guo

et al. 2022

Front. Mol. Neurosci.

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AimDe novo DDX3X variants account for 1–3% of unexplained intellectual disability cases in females and very rarely in males. Yet, the clinical and genetic features of DDX3X neurodevelopmental disorder in the Chinese cohort have not been characterized.MethodA total of 23 Chinese patients (i.e., 22 female and 1 male) with 22 de novo DDX3X deleterious variants were detected among 2,317 probands with unexplained intellectual disability (ID) undertaking whole exome sequencing (WES). The age, sex, genetic data, feeding situation, growth, developmental conditions, and auxiliary examinations of the cohort were collected. The Chinese version of the Gesell Development Diagnosis Scale (GDDS-C) was used to evaluate neurodevelopment of DDX3X patients. The Social Communication Questionnaire (SCQ)-Lifetime version was applied as a primary screener to assess risk for autism spectrum disorder (ASD).ResultA total of 17 DDX3X variants were novel and 22 were de novo. Missense variants overall were only slightly more common than loss-of-function variants and were mainly located in two functional subdomains. The average age of this cohort was 2.67 (±1.42) years old. The overlapping phenotypic spectrum between this cohort and previously described reports includes intellectual disability (23/23, 100%) with varying degrees of severity, muscle tone abnormalities (17/23, 73.9%), feeding difficulties (13/23, 56.5%), ophthalmologic problems (11/23, 47.8%), and seizures (6/23, 26.1%). A total of 15 individuals had notable brain anatomical disruption (15/23, 65.2%), including lateral ventricle enlargement, corpus callosum abnormalities, and delayed myelination. Furthermore, 9 patients showed abnormal electroencephalogram results (9/23, 39.1%). Hypothyroidism was first noted as a novel clinical feature (6/23, 26.1%). The five primary neurodevelopmental domains of GDDS-C in 21 patients were impaired severely, and 13 individuals were above the “at-risk” threshold for ASD.InterpretationAlthough a certain degree of phenotypic overlap with previously reported cohorts, our study described the phenotypic and variation spectrum of 23 additional individuals carrying DDX3X variants in the Chinese population, adding hypothyroidism as a novel finding. We confirmed the importance of DDX3X as a pathogenic gene in unexplained intellectual disability, supporting the necessity of the application of WES in patients with unexplained intellectual disability.

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Developmental and Behavioral Phenotypes in a Mouse Model of DDX3X Syndrome

Cited by 30 publications

References 63 publications

Aberrant cortical development is driven by impaired cell cycle and translational control in a DDX3X syndrome model

Aberrant cortical development is driven by impaired cell cycle and translational control in a DDX3X syndrome model

Aberrant cortical development is driven by impaired cell cycle and translational control in aDDX3Xsyndrome model

Expansion of Clinical and Genetic Spectrum of DDX3X Neurodevelopmental Disorder in 23 Chinese Patients

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