| Great vessel development requires biallelic expression of Chd7 and Tbx1 in pharyngeal ectoderm in mice. | |
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MedLine Citation:
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PMID: 19855134 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Aortic arch artery patterning defects account for approximately 20% of congenital cardiovascular malformations and are observed frequently in velocardiofacial syndrome (VCFS). In the current study, we screened for chromosome rearrangements in patients suspected of VCFS, but who lacked a 22q11 deletion or TBX1 mutation. One individual displayed hemizygous CHD7, which encodes a chromodomain protein. CHD7 haploinsufficiency is the major cause of coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, and ear anomalies/deafness (CHARGE) syndrome, but this patient lacked the major diagnostic features of coloboma and choanal atresia. Because a subset of CHARGE cases also display 22q11 deletions, we explored the embryological relationship between CHARGE and VCSF using mouse models. The hallmark of Tbx1 haploinsufficiency is hypo/aplasia of the fourth pharyngeal arch artery (PAA) at E10.5. Identical malformations were observed in Chd7 heterozygotes, with resulting aortic arch interruption at later stages. Other than Tbx1, Chd7 is the only gene reported to affect fourth PAA development by haploinsufficiency. Moreover, Tbx1+/-;Chd7+/- double heterozygotes demonstrated a synergistic interaction during fourth PAA, thymus, and ear morphogenesis. We could not rescue PAA morphogenesis by restoring neural crest Chd7 expression. Rather, biallelic expression of Chd7 and Tbx1 in the pharyngeal ectoderm was required for normal PAA development. |
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Authors:
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Victoria Randall; Karen McCue; Catherine Roberts; Vanessa Kyriakopoulou; Sarah Beddow; Angela N Barrett; Francesca Vitelli; Katrina Prescott; Charles Shaw-Smith; Koen Devriendt; Erika Bosman; Georg Steffes; Karen P Steel; Subreena Simrick; M Albert Basson; Elizabeth Illingworth; Peter J Scambler |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2009-10-12 |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 119 ISSN: 1558-8238 ISO Abbreviation: J. Clin. Invest. Publication Date: 2009 Nov |
Date Detail:
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Created Date: 2009-11-03 Completed Date: 2009-11-17 Revised Date: 2011-11-24 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: United States |
Other Details:
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Languages: eng Pagination: 3301-10 Citation Subset: AIM; IM |
Affiliation:
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Molecular Medicine Unit, Institute of Child Health, London, United Kingdom. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Alleles* Animals Aorta, Thoracic / embryology* Comparative Genomic Hybridization DNA-Binding Proteins / genetics, metabolism* Ectoderm / metabolism* Gene Expression Regulation, Developmental* Humans Mice Mice, Inbred C57BL Mice, Knockout T-Box Domain Proteins / genetics, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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TCP04006//Telethon; //British Heart Foundation; //Medical Research Council; //Wellcome Trust |
| Chemical | |
Reg. No./Substance:
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0/Chd7 protein, mouse; 0/DNA-Binding Proteins; 0/T-Box Domain Proteins; 0/Tbx1 protein, mouse |
| Comments/Corrections | |
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