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Phenotypic variability in Hey2 −/− mice and absence of HEY2 mutations in patients with congenital heart defects or Alagille syndrome

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Abstract

The genetic alterations leading to congenital heart defects (CHD) are still poorly understood. We and others have recently shown that in mice loss of Hey2 results in a high incidence of fatal ventricular and atrial septal defects, combined with tricuspid stenosis or atresia in some cases. The phenotype has been postulated to resemble human tetralogy of Fallot. Our analysis of CD1 outbred mice suggests that phenotypic consequences of Hey2 loss can be quite variable and dependent on modifier genes as we detected only isolated VSDs with lower prevalence and a significantly reduced mortality rate in this strain. Since Hey2 is one of the few Notch target genes, it is also conceivable that HEY2 mutations may account for cases of Alagille syndrome (AGS: variable combinations of heart, skeleton, eye, and facial malformations and cholestasis), in which the typical mutations of the Notch ligand JAG1 cannot be found. To clarify the role of HEY2 in human CHD and AGS, we screened by direct sequencing 23 children with CHD and 38 patients diagnosed with AGS, which lack mutations in the JAG1 gene. We found two types of silent changes in the coding region: a CTT→CTG transition in exon 3 and a CTG→CTC polymorphism in exon 5. Furthermore, a heterozygous SNP in the splice donor site of exon 4 was detected that is unlikely to disrupt splicing. Although the high incidence and variability of human congenital heart defects implies a multifactorial genetic basis, our results suggest that mutation of HEY2 is not a major contributing factor.

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References

  • D Alagille A Estrada M Hadchouel M Gautier M Odievre et al. (1987) ArticleTitleSyndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases J Pediatr 110 95–200

    Google Scholar 

  • J Donovan A Kordylewska YN Jan MF Utset (2002) ArticleTitleTetralogy of Fallot and other congenital heart defects in Hey2 mutant mice Curr Biol 12 1605–1610 Occurrence Handle10.1016/S0960-9822(02)01149-1 Occurrence Handle1:CAS:528:DC%2BD38XnvVOqs7w%3D Occurrence Handle12372254

    Article  CAS  PubMed  Google Scholar 

  • AG Eroglu F Oztunc L Saltik S Bakari S Dedeoglu et al. (2003) ArticleTitleEvolution of ventricular septal defect with special reference to spontaneous closure rate, subaortic ridge and aortic valve prolapse Pediatr Cardiol 24 31–35 Occurrence Handle10.1007/s00246-002-1345-3 Occurrence Handle1:STN:280:DC%2BD3s%2FmsVaruw%3D%3D Occurrence Handle12360383

    Article  CAS  PubMed  Google Scholar 

  • A Fischer C Leimeister C Winkler N Schumacher B Klamt et al. (2002) ArticleTitleHey bHLH factors in cardiovascular development Cold Spring Harb Symp Quant Biol 67 63–70 Occurrence Handle1:CAS:528:DC%2BD3sXltlGhur4%3D Occurrence Handle12858525

    CAS  PubMed  Google Scholar 

  • A Fischer N Schumacher M Maier M Sendtner M Gessler (2004) ArticleTitleThe Notch target genes Hey1 and Hey2 are required for embryonic vascular development Genes Dev 18 901–911 Occurrence Handle10.1101/gad.291004 Occurrence Handle1:CAS:528:DC%2BD2cXjsFKksLw%3D Occurrence Handle15107403

    Article  CAS  PubMed  Google Scholar 

  • M Gessler KP Knobeloch A Helisch K Amann N Schumacher et al. (2002) ArticleTitleMouse gridlock: no aortic coarctation or deficiency, but fatal cardiac defects in Hey2 −/− mice Curr Biol 12 1601–1604 Occurrence Handle10.1016/S0960-9822(02)01150-8 Occurrence Handle1:CAS:528:DC%2BD38XnvVOqs78%3D Occurrence Handle12372253

    Article  CAS  PubMed  Google Scholar 

  • J Giannakudis A Ropke A Kujat M Krajewska–Walasek H Hughes et al. (2001) ArticleTitleParental mosaicism of JAG1 mutations in families with Alagille syndrome Eur J Hum Genet 9 209–216 Occurrence Handle10.1038/sj.ejhg.5200613 Occurrence Handle1:CAS:528:DC%2BD3MXis1Ohsbs%3D Occurrence Handle11313761

    Article  CAS  PubMed  Google Scholar 

  • T Iso G Chung Y Hamamori L Kedes (2002) ArticleTitleHERP1 is a cell type-specific primary target of Notch J Biol Chem 277 6598–6607 Occurrence Handle10.1074/jbc.M110495200 Occurrence Handle1:CAS:528:DC%2BD38XhvFyqsbw%3D Occurrence Handle11741889

    Article  CAS  PubMed  Google Scholar 

  • L Li ID Krantz Y Deng A Genin AB Banta et al. (1997) ArticleTitleAlagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1 Nat Genet 16 243–251 Occurrence Handle10.1038/ng0797-243 Occurrence Handle1:CAS:528:DyaK2sXktFCqsbc%3D Occurrence Handle9207788

    Article  CAS  PubMed  Google Scholar 

  • MM Maier M Gessler (2000) ArticleTitleComparative analysis of the human and mouse Hey1 promoter: Hey genes are new Notch target genes Biochem Biophys Res Commun 275 652–660 Occurrence Handle10.1006/bbrc.2000.3354 Occurrence Handle1:CAS:528:DC%2BD3cXmtVGmt7c%3D Occurrence Handle10964718

    Article  CAS  PubMed  Google Scholar 

  • B McCright J Lozier T Gridley (2002) ArticleTitleA mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency Development 129 1075–1082 Occurrence Handle1:CAS:528:DC%2BD38XitFygt7w%3D Occurrence Handle11861489

    CAS  PubMed  Google Scholar 

  • DB McElhinney ID Krantz L Bason DA Piccoli KM Emerick et al. (2002) ArticleTitleAnalysis of cardiovascular phenotype and genotype–phenotype correlation in individuals with a JAG1 mutation and/or Alagille syndrome Circulation 106 2567–2574 Occurrence Handle10.1161/01.CIR.0000037221.45902.69 Occurrence Handle12427653

    Article  PubMed  Google Scholar 

  • P Mujica A Morali M Vidailhet M Pierson S Gilgenkrantz (1989) ArticleTitleA case of Alagille’s syndrome with translocation (4;14) (q21;q21) Ann Genet 32 117–119 Occurrence Handle1:STN:280:BiaA3svjtVQ%3D Occurrence Handle2757361

    CAS  PubMed  Google Scholar 

  • T Oda AG Elkahloun BL Pike K Okajima ID Krantz et al. (1997) ArticleTitleMutations in the human Jagged1 gene are responsible for Alagille syndrome Nat Genet 16 235–242 Occurrence Handle10.1038/ng0797-235 Occurrence Handle1:CAS:528:DyaK2sXktFCru70%3D Occurrence Handle9207787

    Article  CAS  PubMed  Google Scholar 

  • A Ropke A Kujat M Graber J Giannakudis I Hansmann (2003) ArticleTitleIdentification of 36 novel Jagged1 (JAG1) mutations in patients with Alagille syndrome Hum Mutat 21 100 Occurrence Handle10.1002/humu.9102

    Article  Google Scholar 

  • Y Sakata CN Kamei H Nakagami R Bronson JK Liao et al. (2002) ArticleTitleVentricular septal defect and cardiomyopathy in mice lacking the transcription factor CHF1/Hey2 Proc Natl Acad Sci USA 99 16197–16202 Occurrence Handle10.1073/pnas.252648999 Occurrence Handle1:CAS:528:DC%2BD38Xps1ensbw%3D Occurrence Handle12454287

    Article  CAS  PubMed  Google Scholar 

  • NB Spinner RP Colliton C Crosnier ID Krantz M Hadchouel et al. (2001) ArticleTitleJagged1 mutations in alagille syndrome Hum Mutat 17 18–33 Occurrence Handle10.1002/1098-1004(2001)17:1<18::AID-HUMU3>3.0.CO;2-T Occurrence Handle1:CAS:528:DC%2BD3MXnsFyitg%3D%3D Occurrence Handle11139239

    Article  CAS  PubMed  Google Scholar 

  • D Srivastava (2001) ArticleTitleGenetic assembly of the heart: implications for congenital heart disease Annu Rev Physiol 63 451–469 Occurrence Handle10.1146/annurev.physiol.63.1.451 Occurrence Handle1:CAS:528:DC%2BD3MXjtFKmtb8%3D Occurrence Handle11181963

    Article  CAS  PubMed  Google Scholar 

  • C Steidl C Leimeister B Klamt M Maier I Nanda et al. (2000) ArticleTitleCharacterization of the human and mouse HEY1, HEY2, and HEYL genes: cloning, mapping, and mutation screening of a new bHLH gene family Genomics 66 195–203 Occurrence Handle10.1006/geno.2000.6200 Occurrence Handle1:CAS:528:DC%2BD3cXktVKnu7k%3D Occurrence Handle10860664

    Article  CAS  PubMed  Google Scholar 

  • R Tandon JE Edwards (1974) ArticleTitleTricuspid atresia. A re-evaluation and classification J Thorac Cardiovasc Surg 67 530–542 Occurrence Handle1:STN:280:CSuC38bpsFw%3D Occurrence Handle4818528

    CAS  PubMed  Google Scholar 

  • SW Turner T Hornung S Hunter (2002) ArticleTitleClosure of ventricular septal defects: a study of factors influencing spontaneous and surgical closure Cardiol Young 12 357–363 Occurrence Handle12206559

    PubMed  Google Scholar 

  • TP Zhong M Rosenberg MA Mohideen B Weinstein MC Fishman (2000) ArticleTitleGridlock, an HLH gene required for assembly of the aorta in zebrafish Science 287 1820–1824 Occurrence Handle10.1126/science.287.5459.1820 Occurrence Handle1:CAS:528:DC%2BD3cXhvVWktro%3D Occurrence Handle10710309

    Article  CAS  PubMed  Google Scholar 

  • TP Zhong S Childs JP Leu MC Fishman (2001) ArticleTitleGridlock signalling pathway fashions the first embryonic artery Nature 414 216–220 Occurrence Handle10.1038/35102599 Occurrence Handle1:CAS:528:DC%2BD3MXosFahsb0%3D Occurrence Handle11700560

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the Deutsche Forschungsgemeinschaft (DFG Ge 539/9). We thank Renate Kottke for skillful technical assistance.

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Authors and Affiliations

  1. Theodor-Boveri-Institute (Biocenter), Physiological Chemistry I, University of Wuerzburg, Am Hubland, D-97074 , Wuerzburg, Germany

    Andreas Fischer, Barbara Klamt, Nina Schumacher & Manfred Gessler

  2. Institute for Human Genetics and Medical Biology, Halle/Saale, Germany

    Christiane Glaeser & Ingo Hansmann

  3. Department of Pediatric Cardiology, University Children’s Hospital, Muenster, Germany

    Hartmut Fenge

Authors
  1. Andreas Fischer
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  2. Barbara Klamt
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  3. Nina Schumacher
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  4. Christiane Glaeser
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  5. Ingo Hansmann
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  6. Hartmut Fenge
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  7. Manfred Gessler
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Corresponding author

Correspondence to Manfred Gessler.

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Fischer, A., Klamt, B., Schumacher, N. et al. Phenotypic variability in Hey2 −/− mice and absence of HEY2 mutations in patients with congenital heart defects or Alagille syndrome. Mamm Genome 15, 711–716 (2004). https://doi.org/10.1007/s00335-004-2389-x

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  • DOI: https://doi.org/10.1007/s00335-004-2389-x

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