{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T04:12:19Z","timestamp":1770437539479,"version":"3.49.0"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2014,6,20]]},"abstract":"<jats:sec>\n            <jats:title>\n              <jats:underline>Rationale<\/jats:underline>\n              :\n            <\/jats:title>\n            <jats:p>\n              22q11 deletion syndrome arises from recombination between low-copy repeats on chromosome 22. Typical deletions result in hemizygosity for\n              <jats:italic>TBX1<\/jats:italic>\n              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.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Objective<\/jats:underline>\n              :\n            <\/jats:title>\n            <jats:p>\n              The transcription factor\n              <jats:italic>HIC2<\/jats:italic>\n              is lost in most distal deletions, as well as in a minority of typical deletions. We used mouse models to test the hypothesis that\n              <jats:italic>HIC2<\/jats:italic>\n              hemizygosity causes congenital heart disease.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Methods and Results<\/jats:underline>\n              :\n            <\/jats:title>\n            <jats:p>\n              We created a genetrap mouse allele of\n              <jats:italic>Hic2.<\/jats:italic>\n              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\n              <jats:italic>Hic2<\/jats:italic>\n              within the\n              <jats:italic>Nkx2.5+<\/jats:italic>\n              and\n              <jats:italic>Mesp1<\/jats:italic>\n              + cardiovascular progenitor lineages. Microarray analysis revealed increased expression of\n              <jats:italic>Bmp10<\/jats:italic>\n              .\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Conclusions<\/jats:underline>\n              :\n            <\/jats:title>\n            <jats:p>\n              Our results demonstrate a novel role for\n              <jats:italic>Hic2<\/jats:italic>\n              in cardiac development.\n              <jats:italic>Hic2<\/jats:italic>\n              is the first gene within the distal 22q11 interval to have a demonstrated haploinsufficient cardiac phenotype in mice. Together our data suggest that\n              <jats:italic>HIC2<\/jats:italic>\n              haploinsufficiency likely contributes to the cardiac defects seen in distal 22q11 deletion syndrome.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.115.303300","type":"journal-article","created":{"date-parts":[[2014,4,19]],"date-time":"2014-04-19T01:07:50Z","timestamp":1397869670000},"page":"23-31","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":33,"title":["<i>HIC2<\/i>\n            Is a Novel Dosage-Dependent Regulator of Cardiac Development Located Within the Distal 22q11 Deletion Syndrome Region"],"prefix":"10.1161","volume":"115","author":[{"given":"Iain M.","family":"Dykes","sequence":"first","affiliation":[{"name":"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 Universit\u00e4t M\u00fcnchen-Weihenstephan, Institute of Developmental Genetics (T.F., W.W.), Helmholtz Zentrum M\u00fcnchen, Neuherberg\/Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), Site Munich, Munich, Germany (W.W.); Munich Cluster for Systems Neurology (SyNergy), Adolf Butenandt..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelly Lammerts","family":"van Bueren","sequence":"additional","affiliation":[{"name":"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 Universit\u00e4t M\u00fcnchen-Weihenstephan, Institute of Developmental Genetics (T.F., W.W.), Helmholtz Zentrum M\u00fcnchen, Neuherberg\/Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), Site Munich, Munich, Germany (W.W.); Munich Cluster for Systems Neurology (SyNergy), Adolf Butenandt..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebekah J.","family":"Ashmore","sequence":"additional","affiliation":[{"name":"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 Universit\u00e4t M\u00fcnchen-Weihenstephan, Institute of Developmental Genetics (T.F., W.W.), Helmholtz Zentrum M\u00fcnchen, Neuherberg\/Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), Site Munich, Munich, Germany (W.W.); Munich Cluster for Systems Neurology (SyNergy), Adolf Butenandt..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Floss","sequence":"additional","affiliation":[{"name":"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 Universit\u00e4t M\u00fcnchen-Weihenstephan, Institute of Developmental Genetics (T.F., W.W.), Helmholtz Zentrum M\u00fcnchen, Neuherberg\/Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), Site Munich, Munich, Germany (W.W.); Munich Cluster for Systems Neurology (SyNergy), Adolf Butenandt..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolfgang","family":"Wurst","sequence":"additional","affiliation":[{"name":"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 Universit\u00e4t M\u00fcnchen-Weihenstephan, Institute of Developmental Genetics (T.F., W.W.), Helmholtz Zentrum M\u00fcnchen, Neuherberg\/Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), Site Munich, Munich, Germany (W.W.); Munich Cluster for Systems Neurology (SyNergy), Adolf Butenandt..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dorota","family":"Szumska","sequence":"additional","affiliation":[{"name":"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 Universit\u00e4t M\u00fcnchen-Weihenstephan, Institute of Developmental Genetics (T.F., W.W.), Helmholtz Zentrum M\u00fcnchen, Neuherberg\/Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), Site Munich, Munich, Germany (W.W.); Munich Cluster for Systems Neurology (SyNergy), Adolf Butenandt..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shoumo","family":"Bhattacharya","sequence":"additional","affiliation":[{"name":"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 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