The CHD4-related syndrome: a comprehensive investigation of the clinical spectrum, genotype–phenotype correlations, and molecular basis

Weiss, Karin; Lazar, Hayley P.; Kurolap, Alina; Martinez, Ariel F.; Paperna, Tamar; Cohen, Lior; Smeland, Marie Falkenberg; Whalen, Sandra; Heide, Solveig; Keren, Boris; Terhal, Pauline; Irving, Melita; Takaku, Motoki; Roberts, John D.; Petrovich, Robert M.; Vergano, Samantha A. Schrier; Kenney, Amy; Hove, Hanne; DeChene, Elizabeth T.; Quinonez, Shane C.; Colin, Estelle; Ziegler, Alban; Rumple, Melissa; Jain, Mahim; Monteil, Danielle; Roeder, Elizabeth; Nugent, Kimberly; Haeringen, Arie van; Gambello, Michael J.; Santani, Avni; Medne, Līvija; Krock, Bryan L.; Skraban, Cara; Zackai, Elaine H.; Dubbs, Holly; Smol, Thomas; Ghoumid, Jamal; Parker, Michael; Wright, Michael J.; Turnpenny, Peter D.; Clayton‐Smith, Jill; Metcalfe, Kay; Kurumizaka, Hitoshi; Gelb, Bruce D.; Feldman, Hagit Baris; Campeau, Philippe M.; Muenke, Maximilian; Wade, Paul A.; Lachlan, Katherine

doi:10.1038/s41436-019-0612-0

Cited by 58 publications

(70 citation statements)

References 37 publications

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“…Further, in light of recent findings reporting hydrocephalus and ventriculomegaly in children with de novo loss-of-function CHD4 mutations (Weiss et al, 2020), we found that the CHD4/NuRD complex is required for the developmental regulation of NKCC1 expression. This connection suggests a possible pathophysiological mechanism whereby lack of CHD4 activity might reduce NKCC1 levels during early development (equivalent to P0-P7 in mice), and lead to insufficient CSF clearance resulting in hydrocephalus.…”

Section: Discussionsupporting

confidence: 58%

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Non-canonical, potassium-driven cerebrospinal fluid clearance

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Sadegh

et al. 2020

Preprint

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Cerebrospinal fluid (CSF) provides vital support for the brain. Abnormal CSF accumulation is deleterious for perinatal neurodevelopment, but how CSF leaves the brain during this critical period is unknown. We found in mice a postnatal neurodevelopmental transition phase featuring precipitous CSF K+ clearance, accompanied by water, through the choroid plexus (ChP). The period corresponds to a human fetal stage when canonical CSF clearance pathways have yet to form and congenital hydrocephalus begins to manifest. Unbiased ChP metabolic and ribosomal profiling highlighted this transition phase with increased ATP yield and activated energy-dependent K+ transporters, in particular the Na+-K+-Cl- and water cotransporter NKCC1. ChP-targeted NKCC1 overexpression enhanced K+-driven CSF clearance and enabled more permissive cerebral hydrodynamics. Moreover, ventriculomegaly in an obstructive hydrocephalus model was improved by ChP-targeted NKCC1 overexpression. Collectively, we identified K+-driven CSF clearance through ChP during a transient but critical neurodevelopmental phase, with translational value for pathologic conditions.

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Section: Discussionsupporting

confidence: 58%

“…3A). De novo loss-of-function CHD4 mutations are implicated in some groups of children with congenital hydrocephalus and ventriculomegaly (Weiss et al, 2020). We found that CHD4 localized to nuclei in mouse ChP epithelial cells beginning at P0 (Fig.…”

Section: Nkcc1 Temporal Regulation Requires Epigenetic Control That Imentioning

confidence: 71%

Non-canonical, potassium-driven cerebrospinal fluid clearance

Fame

Sadegh

et al. 2020

Preprint

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“…In light of recent findings reporting hydrocephalus and ventriculomegaly in children with de novo loss-of-function CHD4 mutations 46 , we found that the CHD4/NuRD complex is required for developmental regulation of NKCC1 expression. This connection suggests a possible pathophysiological mechanism whereby lack of CHD4 activity may reduce NKCC1 levels during early development (equivalent to P0-P7 in mice), and lead to insufficient CSF clearance resulting in hydrocephalus.…”

Section: Discussionmentioning

confidence: 57%

“…3a). De novo loss-of-function CHD4 mutations are implicated in some groups of children with congenital hydrocephalus and ventriculomegaly 46 . We found that CHD4 localized to nuclei in mouse ChP epithelial cells beginning at P0 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Choroid plexus NKCC1 mediates cerebrospinal fluid clearance during mouse early postnatal development

Fame

Sadegh

et al. 2021

Nat Commun

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Cerebrospinal fluid (CSF) provides vital support for the brain. Abnormal CSF accumulation, such as hydrocephalus, can negatively affect perinatal neurodevelopment. The mechanisms regulating CSF clearance during the postnatal critical period are unclear. Here, we show that CSF K+, accompanied by water, is cleared through the choroid plexus (ChP) during mouse early postnatal development. We report that, at this developmental stage, the ChP showed increased ATP production and increased expression of ATP-dependent K+ transporters, particularly the Na+, K+, Cl−, and water cotransporter NKCC1. Overexpression of NKCC1 in the ChP resulted in increased CSF K+ clearance, increased cerebral compliance, and reduced circulating CSF in the brain without changes in intracranial pressure in mice. Moreover, ChP-specific NKCC1 overexpression in an obstructive hydrocephalus mouse model resulted in reduced ventriculomegaly. Collectively, our results implicate NKCC1 in regulating CSF K+ clearance through the ChP in the critical period during postnatal neurodevelopment in mice.

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“…Interestingly, patients carrying mutations in CHD4 actually present with macrocephaly, amongst other characteristics like ID, hearing loss, ventriculomegaly, hypogonadism, palatal abnormalities and facial dysmorphisms that are diagnosed by Sifrim-Hitz-Weiss syndrome [211]. The opposing phenotypes found for brain volume between rodent models and patients might be explained by a gene dosage effect, as for some variants in CHD4 altered ATPase activity levels were found, suggesting a possible gain-offunction phenotype in certain patients [212,213]. Another possibility might be that the NuRD complex function is differentially regulated in humans and mice, as was recently suggested in a study comparing mouse and human pluripotent stem cells [214].…”

Section: Chromatin Remodelling Complexes: Chd Proteins and The Nurd Cmentioning

confidence: 99%

The emerging role of chromatin remodelers in neurodevelopmental disorders: a developmental perspective

Mossink

Negwer

Schubert

et al. 2020

Cell. Mol. Life Sci.

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Neurodevelopmental disorders (NDDs), including intellectual disability (ID) and autism spectrum disorders (ASD), are a large group of disorders in which early insults during brain development result in a wide and heterogeneous spectrum of clinical diagnoses. Mutations in genes coding for chromatin remodelers are overrepresented in NDD cohorts, pointing towards epigenetics as a convergent pathogenic pathway between these disorders. In this review we detail the role of NDD-associated chromatin remodelers during the developmental continuum of progenitor expansion, differentiation, cell-type specification, migration and maturation. We discuss how defects in chromatin remodelling during these early developmental time points compound over time and result in impaired brain circuit establishment. In particular, we focus on their role in the three largest cell populations: glutamatergic neurons, GABAergic neurons, and glia cells. An in-depth understanding of the spatiotemporal role of chromatin remodelers during neurodevelopment can contribute to the identification of molecular targets for treatment strategies.

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The CHD4-related syndrome: a comprehensive investigation of the clinical spectrum, genotype–phenotype correlations, and molecular basis

Cited by 58 publications

References 37 publications

Non-canonical, potassium-driven cerebrospinal fluid clearance

Non-canonical, potassium-driven cerebrospinal fluid clearance

Choroid plexus NKCC1 mediates cerebrospinal fluid clearance during mouse early postnatal development

The emerging role of chromatin remodelers in neurodevelopmental disorders: a developmental perspective

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