TY  - JOUR
AU  - Dykes, Iain M
AU  - van Bueren, Kelly Lammerts
AU  - Ashmore, Rebekah J
AU  - Floss, Thomas
AU  - Wurst, Wolfgang
AU  - Szumska, Dorota
AU  - Bhattacharya, Shoumo
AU  - Scambler, Peter J
TI  - HIC2 is a novel dosage-dependent regulator of cardiac development located within the distal 22q11 deletion syndrome region.
JO  - Circulation research
VL  - 115
IS  - 1
SN  - 0009-7330
CY  - New York, NY
PB  - Assoc.
M1  - DZNE-2020-03754
SP  - 23-31
PY  - 2014
AB  - 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.
KW  - 22q11 Deletion Syndrome: etiology
KW  - 22q11 Deletion Syndrome: genetics
KW  - Adaptor Proteins, Signal Transducing: genetics
KW  - Adaptor Proteins, Signal Transducing: physiology
KW  - Animals
KW  - Bone Morphogenetic Proteins: physiology
KW  - Disease Models, Animal
KW  - Gene Expression Regulation
KW  - Heart: embryology
KW  - Heart Defects, Congenital: etiology
KW  - Humans
KW  - Kruppel-Like Transcription Factors: genetics
KW  - Kruppel-Like Transcription Factors: physiology
KW  - Mice
KW  - Mitogen-Activated Protein Kinase 1: genetics
KW  - Mitogen-Activated Protein Kinase 1: physiology
KW  - Morphogenesis
KW  - Mutagenesis
KW  - Nuclear Proteins: genetics
KW  - Nuclear Proteins: physiology
KW  - T-Box Domain Proteins: genetics
KW  - T-Box Domain Proteins: physiology
KW  - Tumor Suppressor Proteins: genetics
KW  - Tumor Suppressor Proteins: physiology
KW  - Adaptor Proteins, Signal Transducing (NLM Chemicals)
KW  - Bmp10 protein, mouse (NLM Chemicals)
KW  - Bone Morphogenetic Proteins (NLM Chemicals)
KW  - CRKL protein (NLM Chemicals)
KW  - HIC2 protein, human (NLM Chemicals)
KW  - HIC2 protein, mouse (NLM Chemicals)
KW  - Hic1 protein, mouse (NLM Chemicals)
KW  - Kruppel-Like Transcription Factors (NLM Chemicals)
KW  - Nuclear Proteins (NLM Chemicals)
KW  - T-Box Domain Proteins (NLM Chemicals)
KW  - Tbx1 protein, mouse (NLM Chemicals)
KW  - Tumor Suppressor Proteins (NLM Chemicals)
KW  - Mapk1 protein, mouse (NLM Chemicals)
KW  - Mitogen-Activated Protein Kinase 1 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:24748541
DO  - DOI:10.1161/CIRCRESAHA.115.303300
UR  - https://pub.dzne.de/record/137432
ER  -