The NuRD complex and macrocephaly associated neurodevelopmental disorders

Pierson, Tyler Mark; Otero, María Gabriela; Grand, Katheryn; Choi, Andrew; Graham, John M.; Young, Juan I.; Mackay, Joel P.

doi:10.1002/ajmg.c.31752

Cited by 21 publications

(31 citation statements)

References 64 publications

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“…Our functional data accordingly support the idea that Casz1 and the NuRD complex bias RPCs to favor perinatal rod production and to inhibit supernumerary and premature Our data suggest that Casz1 and the NuRD complex are important for biasing RPC output, and thereby control the shape of retinal lineages. The NuRD complex has previously been implicated in neocortical development 37,38 , and human mutations in NuRD genes are associated with neurodevelopmental disorders and macrocephaly 39 . Previous studies also demonstrated that class I histone deacetylases such as Hdac1 and Hdac2 are required to promote rod photoreceptor differentiation [24][25][26] .…”

Section: Discussionmentioning

confidence: 99%

A Casz1–NuRD complex regulates temporal identity transitions in neural progenitors

Mattar

Jolicoeur

Chung

et al. 2021

Sci Rep

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Neural progenitor cells undergo identity transitions during development to ensure the generation different types of neurons and glia in the correct sequence and proportions. A number of temporal identity factors that control these transitions in progenitor competence have been identified, but the molecular mechanisms underlying their function remain unclear. Here, we asked how Casz1, the mammalian orthologue of Drosophila castor, regulates competence during retinal development. We show that Casz1 is required to control the transition between neurogenesis and gliogenesis. Using BioID proteomics, we reveal that Casz1 interacts with the nucleosome remodeling and deacetylase (NuRD) complex in retinal cells. Finally, we show that both the NuRD and the polycomb repressor complexes are required for Casz1 to promote the rod fate and suppress gliogenesis. As additional temporal identity factors have been found to interact with the NuRD complex in other contexts, we propose that these factors might act through this common biochemical process to regulate neurogenesis.

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Section: Discussionmentioning

confidence: 99%

A Casz1–NuRD complex regulates temporal identity transitions in neural progenitors

Mattar

Jolicoeur

Chung

et al. 2021

Sci Rep

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“…Reported literature also corroborates this as many sub-groups of OGID consistently have macrocephaly rather than other somatic overgrowth, like the disorders associated with aberrations in NSD1, NFI proteins, NuRD complex (Pierson et al, 2019;Zenker et al, 2019).…”

Section: Glb1(omim*611458)mentioning

confidence: 59%

Genetic heterogeneity of disorders with overgrowth and intellectual disability: Experience from a center in North India

Moirangthem

Mandal

Saxena

et al. 2021

American J of Med Genetics Pt A

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Overgrowth, defined as height and/or OFC ≥ +2SD, characterizes a subset of patients with syndromic intellectual disability (ID). Many of the disorders with overgrowth and ID (OGID) are rare and the full phenotypic and genotypic spectra have not been unraveled. This study was undertaken to characterize the phenotypic and genotypic profile of patients with OGID. Patients with OGID were ascertained from the cohort of patients who underwent cytogenetic microarray (CMA) and/or exome sequencing (ES) at our center over a period of 6 years. Thirty-one subjects (six females) formed the study group with ages between 3.5 months and 13 years. CMA identified pathogenic deletions in two patients. In another 11 patients, a disease causing variant was detected by ES. The spectrum of disorders encompassed aberrations in genes involved in the two main pathways associated with OGID. These were genes involved in epigenetic regulation like NSD1, NFIX, FOXP1, and those in the PI3K-AKT pathway like PTEN, AKT3, TSC2, PPP2R5D. Five novel pathogenic variants were added by this study. NSD1-related Sotos syndrome was the most common disorder, seen in five patients. A causative variant was identified in 61.5% of patients who underwent only ES compared to the low yield of 11.1% in the CMA group. The molecular etiology could be confirmed in 13 subjects with OGID giving a diagnostic yield of 42%. The major burden was formed by autosomal dominant monogenic disorders. Hence, ES maybe a better first-tier genomic test rather than CMA in OGID.

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“…CHD5 comprises nine protein domains: an N-terminal domain of chromo domain-associated helicases (CHDNT), two PHD domains (PHD1 and PHD2) and two chromodomains (Chd1 and Chd2) important for histone binding, one bipartite Helicase domain with ATPase catalytic activity, two conserved Domains with Unknown Function (DUF1087 and DUF1086), and a C-terminal domain B of chromo domain-associated CHD-like helicases (CHDCT2) mediating the interaction with GATA2D (Pierson et al 2019 ) (Fig. 2 a).…”

Section: Resultsmentioning

confidence: 99%

Missense and truncating variants in CHD5 in a dominant neurodevelopmental disorder with intellectual disability, behavioral disturbances, and epilepsy

et al. 2021

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Located in the critical 1p36 microdeletion region, the chromodomain helicase DNA-binding protein 5 (CHD5) gene encodes a subunit of the nucleosome remodeling and deacetylation (NuRD) complex required for neuronal development. Pathogenic variants in six of nine chromodomain (CHD) genes cause autosomal dominant neurodevelopmental disorders, while CHD5-related disorders are still unknown. Thanks to GeneMatcher and international collaborations, we assembled a cohort of 16 unrelated individuals harboring heterozygous CHD5 variants, all identified by exome sequencing. Twelve patients had de novo CHD5 variants, including ten missense and two splice site variants. Three familial cases had nonsense or missense variants segregating with speech delay, learning disabilities, and/or craniosynostosis. One patient carried a frameshift variant of unknown inheritance due to unavailability of the father. The most common clinical features included language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%). Epilepsy types were variable, with West syndrome observed in three patients, generalized tonic–clonic seizures in two, and other subtypes observed in one individual each. Our findings suggest that, in line with other CHD-related disorders, heterozygous CHD5 variants are associated with a variable neurodevelopmental syndrome that includes intellectual disability with speech delay, epilepsy, and behavioral problems as main features.

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The NuRD complex and macrocephaly associated neurodevelopmental disorders

Cited by 21 publications

References 64 publications

A Casz1–NuRD complex regulates temporal identity transitions in neural progenitors

A Casz1–NuRD complex regulates temporal identity transitions in neural progenitors

Genetic heterogeneity of disorders with overgrowth and intellectual disability: Experience from a center in North India

Missense and truncating variants in CHD5 in a dominant neurodevelopmental disorder with intellectual disability, behavioral disturbances, and epilepsy

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