title: Phenotypic variability in Hey2 -/- mice and absence of HEY2 mutations in patients with congenital heart defects or Alagille syndrome.
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.
authors.affiliation: Theodor-Boveri-Institute (Biocenter), Physiological Chemistry I, University of Wuerzburg, D-97074, Am Hubland, Wuerzburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Fischer
authors.forename: Barbara
authors.initials: B
authors.lastname: Klamt
authors.forename: Nina
authors.initials: N
authors.lastname: Schumacher
authors.forename: Christiane
authors.initials: C
authors.lastname: Glaeser
authors.forename: Ingo
authors.initials: I
authors.lastname: Hansmann
authors.forename: Hartmut
authors.initials: H
authors.lastname: Fenge
authors.forename: Manfred
authors.initials: M
authors.lastname: Gessler
mesh_terms: D000293:Adolescent; D016738:Alagille Syndrome / Q000235:genetics* / Q000473:pathology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000737:chemistry / Q000235:genetics; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007223:Infant; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018895:Microsatellite Repeats / Q000235:genetics; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D000072099:Serrate-Jagged Proteins
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D004247:DNA; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D012097:Repressor Proteins; D000072099:Serrate-Jagged Proteins; C405693:HEY2 protein, human; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse