+ Resolve Article
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter

+ Translate
+ Subscribe to Site Feed
GeoScience Most Shared ContentMost Shared Content

HIC2 is a novel dosage-dependent regulator of cardiac development located within the distal 22q11 deletion syndrome region

, : HIC2 is a novel dosage-dependent regulator of cardiac development located within the distal 22q11 deletion syndrome region. Circulation Research 115(1): 23-31

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.


PMID: 24748541

DOI: 10.1161/CIRCRESAHA.115.303300

Other references

Huang, A.Y.; Yu, D.; Davis, L.K.; Sul, J.Hoon.; Tsetsos, F.; Ramensky, V.; Zelaya, I.; Ramos, E.Marisa.; Osiecki, L.; Chen, J.A.; McGrath, L.M.; Illmann, C.; Sandor, P.; Barr, C.L.; Grados, M.; Singer, H.S.; Nöthen, M.M.; Hebebrand, J.; King, R.A.; Dion, Y.; Rouleau, G.; Budman, C.L.; Depienne, C.; Worbe, Y.; Hartmann, A.; Müller-Vahl, K.R.; Stuhrmann, M.; Aschauer, H.; Stamenkovic, M.; Schloegelhofer, M.; Konstantinidis, A.; Lyon, G.J.; McMahon, W.M.; Barta, C.; Tarnok, Z.; Nagy, P.; Batterso, 2017: Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome. Tourette syndrome (TS) is a model neuropsychiatric disorder thought to arise from abnormal development and/or maintenance of cortico-striato-thalamo-cortical circuits. TS is highly heritable, but its underlying genetic causes are still elusive, an...

McLean, R.C.; Hirsch, G.A.; Becker, L.C.; Kasch-Semenza, L.; Gerstenblith, G.; Schulman, S.P., 2011: Polymorphisms of the beta adrenergic receptor predict left ventricular remodeling following acute myocardial infarction. Prior studies demonstrate an association between specific beta-adrenergic receptor (?-AR) polymorphisms and clinical outcomes in patients with chronic heart failure and following acute coronary syndromes. The underlying mechanism may be due to dif...

Okawa, K.; Miyoshi, T.; Tsukuda, S.; Hara, S.; Matsuo, N.; Nishibe, N.; Sogo, M.; Okada, T.; Nosaka, K.; Sakane, K.; Doi, M.; Morita, H.; Ito, H., 2017: Differences in endothelial dysfunction induced by paroxysmal and persistent atrial fibrillation: Insights from restoration of sinus rhythm by catheter ablation. Atrial fibrillation (AF) is associated with endothelial dysfunction. Studies have shown the incidence of cardiovascular events to be greater in patients with persistent AF (PeAF) than paroxysmal AF (PAF). The aim of this study was to investigate w...

Rowe Winthrop A.; Mejia Vicotr M.; Cumberlidge John T.; Mattson Louis A., 1976: Geology of the Nickel Mountain Mine, Riddle, Oregon. Pages 25-46 1976

Lauritzen, C., 1977: Estrogen thearpy in practice. 3. Estrogen preparations and combination preparations. Fortschritte der Medizin 95(21): 1388-1392

Boeke, M.C., 1950: New patterns in teaching communicable disease nursing. American Journal of Nursing 50(6): 374-377

Holmes, R.R.; Chandrasekaran, A.; Timosheva, N.V.; Day, R.O., 2003: Hypervalent oxyphosphoranes as a model for phosphoryl transfer enzymes. Abstracts of Papers American Chemical Society 225(1-2): INOR 711

Gerritzen, F., 1937: The 24-hour rhythm in chlorine excretion. The hourly volume of urine and Cl excretion of 35 healthy students was followed over a period of 27 hours, during which all the subjects received exactly the same food each hour. A parallelism was found between Cl excretion and urinary volume, and...

Bushnell, J., 1929: The normal multiple sprouting of seed potatoes. The sprouting habit of sets of the Russet Rural potato variety was studied in successive plantings in the greenhouse and in the field. The results demonstrated that the rest period extended to December or early January, that single sprouts were pr...

Fogel' , A.A.; Zakharov, V.S., 1991: Type and size series of industrial tractors. Three types of tractors manufactured by the Cheboksarskii plant are presented: T-25.01 (class 25), T-500 (class 35) and T-50.01 (class 50); their technical parameters and schematic diagrams are given. Performance of the three tractor types is asse...