Title: Great vessel development requires biallelic expression of Chd7 and Tbx1 in pharyngeal ectoderm in mice
Authors: Randall, Victoria ×
McCue, Karen
Roberts, Catherine
Kyriakopoulou, Vanessa
Beddow, Sarah
Barrett, Angela N
Vitelli, Francesca
Prescott, Katrina
Shaw-Smith, Charles
Devriendt, Koenraad
Bosman, Erika
Steffes, Georg
Steel, Karen P
Simrick, Subreena
Basson, M Albert
Illingworth, Elizabeth
Scambler, Peter J #
Issue Date: Nov-2009
Publisher: American Society for Clinical Investigation
Series Title: Journal of Clinical Investigation vol:119 issue:11 pages:3301-3310
Abstract: 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.
ISSN: 0021-9738
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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