Phenotypic variability in Hey2 -/- mice and absence of HEY2 mutations in patients with congenital heart defects or Alagille syndrome
| Autor: | Hartmut Fenge, Andreas Fischer, Barbara Klamt, Manfred Gessler, Christiane Glaeser, Nina Schumacher, Ingo Hansmann |
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| Rok vydání: | 2004 |
| Předmět: |
Heart Defects
Congenital JAG1 Adolescent Biology medicine.disease_cause Polymerase Chain Reaction Polymorphism Single Nucleotide Atrial septal defects Exon Mice Alagille syndrome Genetics medicine Basic Helix-Loop-Helix Transcription Factors Animals Humans Point Mutation Serrate-Jagged Proteins HEY2 Child Tetralogy of Fallot Mice Knockout Mutation Calcium-Binding Proteins Infant Membrane Proteins DNA Sequence Analysis DNA medicine.disease Phenotype Alagille Syndrome Mice Inbred C57BL Repressor Proteins Child Preschool Intercellular Signaling Peptides and Proteins Jagged-1 Protein Microsatellite Repeats |
| Zdroj: | Mammalian genome : official journal of the International Mammalian Genome Society. 15(9) |
| ISSN: | 0938-8990 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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