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@ARTICLE{Dykes:137432,
author = {Dykes, Iain M and van Bueren, Kelly Lammerts and Ashmore,
Rebekah J and Floss, Thomas and Wurst, Wolfgang and Szumska,
Dorota and Bhattacharya, Shoumo and Scambler, Peter J},
title = {{HIC}2 is a novel dosage-dependent regulator of cardiac
development located within the distal 22q11 deletion
syndrome region.},
journal = {Circulation research},
volume = {115},
number = {1},
issn = {0009-7330},
address = {New York, NY},
publisher = {Assoc.},
reportid = {DZNE-2020-03754},
pages = {23-31},
year = {2014},
abstract = {22q11 deletion syndrome arises from recombination between
low-copy repeats on chromosome 22. Typical deletions result
in hemizygosity for TBX1 associated with congenital
cardiovascular disease. Deletions distal to the typically
deleted region result in a similar cardiac phenotype but
lack in extracardiac features of the syndrome, suggesting
that a second haploinsufficient gene maps to this
interval.The transcription factor HIC2 is lost in most
distal deletions, as well as in a minority of typical
deletions. We used mouse models to test the hypothesis that
HIC2 hemizygosity causes congenital heart disease.We created
a genetrap mouse allele of Hic2. The genetrap reporter was
expressed in the heart throughout the key stages of cardiac
morphogenesis. Homozygosity for the genetrap allele was
embryonic lethal before embryonic day E10.5, whereas the
heterozygous condition exhibited a partially penetrant late
lethality. One third of heterozygous embryos had a cardiac
phenotype. MRI demonstrated a ventricular septal defect with
over-riding aorta. Conditional targeting indicated a
requirement for Hic2 within the Nkx2.5+ and Mesp1+
cardiovascular progenitor lineages. Microarray analysis
revealed increased expression of Bmp10.Our results
demonstrate a novel role for Hic2 in cardiac development.
Hic2 is the first gene within the distal 22q11 interval to
have a demonstrated haploinsufficient cardiac phenotype in
mice. Together our data suggest that HIC2 haploinsufficiency
likely contributes to the cardiac defects seen in distal
22q11 deletion syndrome.},
keywords = {22q11 Deletion Syndrome: etiology / 22q11 Deletion
Syndrome: genetics / Adaptor Proteins, Signal Transducing:
genetics / Adaptor Proteins, Signal Transducing: physiology
/ Animals / Bone Morphogenetic Proteins: physiology /
Disease Models, Animal / Gene Expression Regulation / Heart:
embryology / Heart Defects, Congenital: etiology / Humans /
Kruppel-Like Transcription Factors: genetics / Kruppel-Like
Transcription Factors: physiology / Mice / Mitogen-Activated
Protein Kinase 1: genetics / Mitogen-Activated Protein
Kinase 1: physiology / Morphogenesis / Mutagenesis / Nuclear
Proteins: genetics / Nuclear Proteins: physiology / T-Box
Domain Proteins: genetics / T-Box Domain Proteins:
physiology / Tumor Suppressor Proteins: genetics / Tumor
Suppressor Proteins: physiology / Adaptor Proteins, Signal
Transducing (NLM Chemicals) / Bmp10 protein, mouse (NLM
Chemicals) / Bone Morphogenetic Proteins (NLM Chemicals) /
CRKL protein (NLM Chemicals) / HIC2 protein, human (NLM
Chemicals) / HIC2 protein, mouse (NLM Chemicals) / Hic1
protein, mouse (NLM Chemicals) / Kruppel-Like Transcription
Factors (NLM Chemicals) / Nuclear Proteins (NLM Chemicals) /
T-Box Domain Proteins (NLM Chemicals) / Tbx1 protein, mouse
(NLM Chemicals) / Tumor Suppressor Proteins (NLM Chemicals)
/ Mapk1 protein, mouse (NLM Chemicals) / Mitogen-Activated
Protein Kinase 1 (NLM Chemicals)},
cin = {AG Wurst},
ddc = {610},
cid = {I:(DE-2719)1140001},
pnm = {342 - Disease Mechanisms and Model Systems (POF3-342)},
pid = {G:(DE-HGF)POF3-342},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:24748541},
doi = {10.1161/CIRCRESAHA.115.303300},
url = {https://pub.dzne.de/record/137432},
}