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

Mammalian Genome : Official Journal of the International Mammalian Genome Society
Andreas FischerM Gessler

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 h...Continue Reading

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Citations

Dec 25, 2009·Pediatric Cardiology·Cornelia WieseManfred Gessler
Jun 26, 2007·Nucleic Acids Research·Andreas Fischer, Manfred Gessler
Jan 1, 2010·Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association·Rajesh ShrivastavaVandse Aithal
Apr 24, 2012·Circulation. Cardiovascular Genetics·Huiqing LiRoger H Reeves
Aug 23, 2012·Development·Chien-Jung LinChing-Pin Chang
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Aug 2, 2005·Seminars in Cell & Developmental Biology·Jason Z Stoller, Jonathan A Epstein
Feb 17, 2009·Developmental Cell·Sarah De Val, Brian L Black
Sep 23, 2016·Cardiology in the Young·Manchen GaoJinghao Zheng
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Feb 13, 2008·American Journal of Medical Genetics. Part a·Inaam El-RassyGeorges Nemer
Oct 18, 2019·The European Respiratory Journal·Soula DanopoulosDenise Al Alam
Aug 21, 2020·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Eva S van WalreeInge B Mathijssen

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