title: HIC2 is a novel dosage-dependent regulator of cardiac development located within the distal 22q11 deletion syndrome region.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: 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 Institute, Ludwig-Maximilians-Universität München, Munich, Germany (W.W.); and Departments of Cardiovascular Medicine (D.S., S.B.) and Cardiovascular Medicine (I.M.D.), University of Oxford, Wellcome Trust Centre for Human Genetics, Headington, Oxford, United Kingdom.
authors.forename: Iain M
authors.initials: IM
authors.lastname: Dykes
authors.affiliation: 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 Institute, Ludwig-Maximilians-Universität München, Munich, Germany (W.W.); and Departments of Cardiovascular Medicine (D.S., S.B.) and Cardiovascular Medicine (I.M.D.), University of Oxford, Wellcome Trust Centre for Human Genetics, Headington, Oxford, United Kingdom.
authors.forename: Kelly Lammerts
authors.initials: KL
authors.lastname: van Bueren
authors.affiliation: 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 Institute, Ludwig-Maximilians-Universität München, Munich, Germany (W.W.); and Departments of Cardiovascular Medicine (D.S., S.B.) and Cardiovascular Medicine (I.M.D.), University of Oxford, Wellcome Trust Centre for Human Genetics, Headington, Oxford, United Kingdom.
authors.forename: Rebekah J
authors.initials: RJ
authors.lastname: Ashmore
authors.affiliation: 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 Institute, Ludwig-Maximilians-Universität München, Munich, Germany (W.W.); and Departments of Cardiovascular Medicine (D.S., S.B.) and Cardiovascular Medicine (I.M.D.), University of Oxford, Wellcome Trust Centre for Human Genetics, Headington, Oxford, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: Floss
authors.affiliation: 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 Institute, Ludwig-Maximilians-Universität München, Munich, Germany (W.W.); and Departments of Cardiovascular Medicine (D.S., S.B.) and Cardiovascular Medicine (I.M.D.), University of Oxford, Wellcome Trust Centre for Human Genetics, Headington, Oxford, United Kingdom.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.affiliation: 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 Institute, Ludwig-Maximilians-Universität München, Munich, Germany (W.W.); and Departments of Cardiovascular Medicine (D.S., S.B.) and Cardiovascular Medicine (I.M.D.), University of Oxford, Wellcome Trust Centre for Human Genetics, Headington, Oxford, United Kingdom.
authors.forename: Dorota
authors.initials: D
authors.lastname: Szumska
authors.affiliation: 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 Institute, Ludwig-Maximilians-Universität München, Munich, Germany (W.W.); and Departments of Cardiovascular Medicine (D.S., S.B.) and Cardiovascular Medicine (I.M.D.), University of Oxford, Wellcome Trust Centre for Human Genetics, Headington, Oxford, United Kingdom.
authors.forename: Shoumo
authors.initials: S
authors.lastname: Bhattacharya
authors.affiliation: 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 Institute, Ludwig-Maximilians-Universität München, Munich, Germany (W.W.); and Departments of Cardiovascular Medicine (D.S., S.B.) and Cardiovascular Medicine (I.M.D.), University of Oxford, Wellcome Trust Centre for Human Genetics, Headington, Oxford, United Kingdom. p.scambler@ucl.ac.uk.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scambler
mesh_terms: D058165:22q11 Deletion Syndrome / Q000209:etiology* / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000502:physiology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000209:etiology; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000502:physiology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000502:physiology; D009024:Morphogenesis; D016296:Mutagenesis; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology; D020825:T-Box Domain Proteins / Q000235:genetics / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C119152:Bmp10 protein, mouse; D019485:Bone Morphogenetic Proteins; C082869:CRKL protein; C436951:HIC2 protein, human; C000590644:HIC2 protein, mouse; C096870:Hic1 protein, mouse; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D020825:T-Box Domain Proteins; C491573:Tbx1 protein, mouse; D025521:Tumor Suppressor Proteins; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1
keywords: 22q11 deletion syndrome; HIC2 protein, human; Mesp1 protein, mouse; developmental biology; genetics; heart septal defects, ventricular; models, animal