Inappropriate p53 activation during development induces features of CHARGE syndrome

Nostrand, Jeanine L. Van; Brady, Colleen A.; Jung, Heiyoun; Fuentes, Daniel; Kozak, Margaret M.; Johnson, Thomas M.; Lin, Chieh Yu; Lin, Chien Jung; Swiderski, Donald L.; Vogel, Hannes; Bernstein, Jonathan A.; Attié‐Bitach, Tania; Chang, Ching Pin; Wysocka, Joanna; Martin, Donna M.; Attardi, Laura D.

doi:10.1038/nature13585

Cited by 119 publications

(137 citation statements)

References 35 publications

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“…Knockdown of Chd8 by shRNA does not alter the morphology or neural ectodermal markers of neural progenitors derived from human iPS cells, but does significantly impair their gene expression [74]. A very recent study also showed that CHD7 binds to and represses p53, suggesting some CHD proteins (at least those in the third subclass) may share common downstream mechanisms, interacting factors, and target genes [83]. Thus, CHD7 and CHD8 not only share common mechanistic pathways but also make unique contributions to developmental events in a wide variety of tissues and cell types.…”

Section: Chd Proteins In Human Diseasementioning

confidence: 98%

Chromodomain Helicase DNA-Binding Proteins in Stem Cells and Human Developmental Diseases

Micucci

Sperry

Martin

2015

Stem Cells and Development

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Section: Chd Proteins In Human Diseasementioning

confidence: 98%

Chromodomain Helicase DNA-Binding Proteins in Stem Cells and Human Developmental Diseases

Micucci

Sperry

Martin

2015

Stem Cells and Development

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“…Additional experiments show that p53 heterozygosity can partially rescue the phenotypes in CHD7-null mouse embryos (van Nostrand et al, 2014). Interestingly, symptoms of Tbx1 deficiency can also be rescued by reduction of p53 levels (Caprio & Baldini, 2014).…”

Section: Chd7 Protein Complexes and Their Function In Development Amentioning

confidence: 99%

“…Van Nostrand et al (2014) observed that a knock-in mutant mouse strain with heterozygous expression of a stabilized and transcriptionally inactive variant of the tumor-suppressor protein p53 exhibits a phenotype typical for CHARGE syndrome. Furthermore, the authors showed that Chd7-null mouse NC cells and fibroblasts from patients with CHARGE syndrome have increased p53 signaling and that Chd7 binds to the p53 promotor to repress p53 gene expression (van Nostrand et al, 2014).…”

Section: Chd7 Protein Complexes and Their Function In Development Amentioning

confidence: 99%

CHARGEd with neural crest defects

Pauli

Bajpai

Borchers

2017

American J of Med Genetics Pt C

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Neural crest cells are highly migratory pluripotent cells that give rise to diverse derivatives including cartilage, bone, smooth muscle, pigment, and endocrine cells as well as neurons and glia. Abnormalities in neural crest‐derived tissues contribute to the etiology of CHARGE syndrome, a complex malformation disorder that encompasses clinical symptoms like coloboma, heart defects, atresia of the choanae, retarded growth and development, genital hypoplasia, ear anomalies, and deafness. Mutations in the chromodomain helicase DNA‐binding protein 7 (CHD7) gene are causative of CHARGE syndrome and loss‐of‐function data in different model systems have firmly established a role of CHD7 in neural crest development. Here, we will summarize our current understanding of the function of CHD7 in neural crest development and discuss possible links of CHARGE syndrome to other developmental disorders.

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“…Recently, inappropriate activation of p53 during development was linked with the pathogenesis of CHARGE syndrome, a disorder characterized by abnormalities including developmental delay, heart defects, coloboma, cranial nerve abnormalities, choanal atresia, and inner ear abnormalities. 44,45 The phenotypic spectrum in the CHARGE syndrome mouse model shows substantial overlap with the ASPP2-deficient mice (including NTDs, short lower jaw, coloboma, and heart defects), suggesting that dysregulated p53 activity might be responsible for these phenotypes in ASPP2-deficient mice. However, while p53-deficient and p53-overactivated embryos show primarily exencephaly, 14,44 ASPP2-deficient embryos develop mainly spina bifida or craniorachischisis, pointing to the importance of p53-independent functions of ASPP2.…”

Section: δ3mentioning

confidence: 99%

“…Therefore, the concomitant deletion of multiple haploinsufficient genes might exacerbate the phenotype, as is the case in other known contiguous gene deletion syndromes. 44,45 At the protein level, the ability of ASPP2 to regulate apicobasal polarity and p53-dependent apoptosis is likely important for its role in neural tube closure. Recently, inappropriate activation of p53 during development was linked with the pathogenesis of CHARGE syndrome, a disorder characterized by abnormalities including developmental delay, heart defects, coloboma, cranial nerve abnormalities, choanal atresia, and inner ear abnormalities.…”

Section: δ3mentioning

confidence: 99%

ASPP2 deficiency causes features of 1q41q42 microdeletion syndrome

et al. 2016

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Chromosomal abnormalities are implicated in a substantial number of human developmental syndromes, but for many such disorders little is known about the causative genes. The recently described 1q41q42 microdeletion syndrome is characterized by characteristic dysmorphic features, intellectual disability and brain morphological abnormalities, but the precise genetic basis for these abnormalities remains unknown. Here, our detailed analysis of the genetic abnormalities of 1q41q42 microdeletion cases identified TP53BP2, which encodes apoptosis-stimulating protein of p53 2 (ASPP2), as a candidate gene for brain abnormalities. Consistent with this, Trp53bp2-deficient mice show dilation of lateral ventricles resembling the phenotype of 1q41q42 microdeletion patients. Trp53bp2 deficiency causes 100% neonatal lethality in the C57BL/6 background associated with a high incidence of neural tube defects and a range of developmental abnormalities such as congenital heart defects, coloboma, microphthalmia, urogenital and craniofacial abnormalities. Interestingly, abnormalities show a high degree of overlap with 1q41q42 microdeletion-associated abnormalities. These findings identify TP53BP2 as a strong candidate causative gene for central nervous system (CNS) defects in 1q41q42 microdeletion syndrome, and open new avenues for investigation of the mechanisms underlying CNS abnormalities.

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Inappropriate p53 activation during development induces features of CHARGE syndrome

Cited by 119 publications

References 35 publications

Chromodomain Helicase DNA-Binding Proteins in Stem Cells and Human Developmental Diseases

Chromodomain Helicase DNA-Binding Proteins in Stem Cells and Human Developmental Diseases

CHARGEd with neural crest defects

ASPP2 deficiency causes features of 1q41q42 microdeletion syndrome

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