Great vessel development requires biallelic expression of Chd7 and Tbx1 in pharyngeal ectoderm in mice.
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.
Molecular Medicine Unit, Institute of Child Health, London, United Kingdom.
Victoria
V
Randall
Karen
K
McCue
Catherine
C
Roberts
Vanessa
V
Kyriakopoulou
Sarah
S
Beddow
Angela N
AN
Barrett
Francesca
F
Vitelli
Katrina
K
Prescott
Charles
C
Shaw-Smith
Koen
K
Devriendt
Erika
E
Bosman
Georg
G
Steffes
Karen P
KP
Steel
Subreena
S
Simrick
M Albert
MA
Basson
Elizabeth
E
Illingworth
Peter J
PJ
Scambler
D000483:Alleles; D000818:Animals; D001013:Aorta, Thoracic / Q000196:embryology*; D055028:Comparative Genomic Hybridization; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004475:Ectoderm / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*
C507367:Chd7 protein, mouse; D004268:DNA-Binding Proteins; D020825:T-Box Domain Proteins; C491573:Tbx1 protein, mouse