HIC2 Is a Novel Dosage-Dependent Regulator of Cardiac Development Located Within the Distal 22q11 Deletion Syndrome Region
Open accessAbstract
Rationale : 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. Objective : 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. Methods and Results : 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 . Conclusions : 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.
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HIC1, HIC2, GZF1, OSR1, OSR2, and SALL4 could contribute to developmental abnormalities in fetuses exposed to thalidomide.
“and could contribute to developmental abnormalities in fetuses exposed to thalidomide (25–30).”
From Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN (2018) · cites this paper as [26]
The Hic2 Has a Haploinsufficient Cardiovascular Phenotype section (page unavailable) reports developmental delay and cardiac defects in Hic2-mutant mouse embryos, supporting a developmental role for HIC2. The paper does not address thalidomide exposure or establish that HIC2 contributes to abnormalities in exposed fetuses; it also does not establish the proposed roles of GZF1, OSR1, OSR2, or SALL4. (LLM, conf=0.86)
Experimental — accuracy not yet measuredHIC1, HIC2, GZF1, OSR1, OSR2, and SALL4 have all been implicated in development.
“HIC1, HIC2, GZF1, OSR1, OSR2, and SALL4 have all been implicated in development”
From Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN (2018) · cites this paper as [26]
The introduction describes developmental defects in mice lacking Hic1 and a role for Hic2 in embryonic cardiovascular development; the cardiac-development results further support Hic2’s role. The cited paper does not establish the claim for GZF1, OSR1, OSR2, or SALL4 (searched those gene names and developmental roles). (LLM, conf=0.88)
Experimental — accuracy not yet measuredSeveral ZFs identified as degraded in functional experiments, or in vitro binders that could be targeted with further drug development, have been implicated in human disease.
“Several of the ZFs identified as degraded in functional experiments, or in vitro binders that could be targeted with further drug development, have been implicated in human disease.”
From Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN (2018) · cites this paper as [26]
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McDonald-McGinn, D. M., Sullivan, K. E., Marino, B., Philip, N., Swillen, A., Vorstman, J. A. S., Zackai, E. H., Emanuel, B. S., Vermeesch, J. R., Morrow, B. E., et al. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.71 · Cited by 2,236 · see citing works
Self-citationDefining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN
Sievers, Q. L., Petzold, G., Bunker, R. D., Renneville, A., Słabicki, M., Liddicoat, B. J., Abdulrahman, W., Mikkelsen, T., Ebert, B. L., & Thomä, N. H. (2018) · Science · doi:10.1126/science.aat0572 · Cited by 537 · see citing works
Molecular genetics of 22q11.2 deletion syndrome
Morrow, B. E., McDonald‐McGinn, D. M., Emanuel, B. S., Vermeesch, J. R., & Scambler, P. J. (2018) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.40504 · Cited by 137 · see citing works
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- Authors
- Dykes, I. M., van Bueren, K. L., Ashmore, R. J., Floss, T., Wurst, W., Szumska, D., Bhattacharya, S., & Scambler, P. J.
- Affiliations
- Centre for Human Genetics (GB)
- From the Molecular Medicine Unit, Institute of Child Health, University College London, London, United Kingdom (I.M.D., K.L.v.B., R.J.A., P.J.S.); Institute of Developmental Genetics (T.F., W.W.) and Technische Universität München-Weihenstephan, Institute of Developmental Genetics (T.F., W.W.), Helmholtz Zentrum München, Neuherberg/Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), Site Munich, Munich, Germany (W.W.); Munich Cluster for Systems Neurology (SyNergy), Adolf Butenandt...
- ORCID
- Venue
- Circulation Research
- Published
- 2014-06-20
- Volume
- 115
- Issue
- 1
- Pages
- 23-31
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2115542371
- Cited by
- 33
- References
- 45
- Citations by year
- 2025: 5 · 2024: 2 · 2023: 2 · 2022: 4 · 2021: 1 · 2019: 4 · 2018: 3 · 2017: 5 · 2016: 2 · 2015: 5
- FWCI
- 1.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Explore Bristol Research (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Site cant be reached (submittedVersion)
- DZNE Pub (submittedVersion)
- Bristol Research (University of Bristol) (submittedVersion)
- Funders
- State University of New York
- Wellcome Trust (090532)
- British Heart Foundation (PG/10/17/28553, CH/09/003, PG/09/065/27893, RG/10/17/28553, PG/07/045/22690)
- European Commission
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- 22q11.2 deletion syndrome, congenital heart disease, heart development, haploinsufficiency, ventricular septal defect, Nkx2.5, Mesp1, cardiovascular progenitor cells, BMP10, embryonic lethality
- MeSH terms
- Animals, Disease Models, Animal, Gene Expression Regulation, Heart, Heart Defects, Congenital, Humans, Morphogenesis, Nuclear Proteins, Mutagenesis, Bone Morphogenetic Proteins, Mitogen-Activated Protein Kinase 1, T-Box Domain Proteins, Tumor Suppressor Proteins, Adaptor Proteins, Signal Transducing, Mice, Kruppel-Like Transcription Factors, 22q11 Deletion Syndrome
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