Penetrance of Congenital Heart Disease in a Mouse Model of Down Syndrome Depends on a Trisomic Potentiator of a Disomic Modifier

Down syndrome (DS) is a significant risk factor for congenital heart disease (CHD), increasing the incidence 50 times over the general population. However, half of people with DS have a normal heart and thus trisomy 21 is not sufficient to cause CHD by itself. Ts65Dn mice are trisomic for orthologs of >100 Hsa21 genes, and their heart defect frequency is significantly higher than their euploid littermates. Introduction of a null allele of Creld1 into Ts65Dn increases the penetrance of heart defects significantly. However, this increase was not seen when the Creld1 null allele was introduced into Ts1Cje, a mouse that is trisomic for about two thirds of the Hsa21 orthologs that are triplicated in Ts65Dn. Among the 23 genes present in three copies in Ts65Dn but not Ts1Cje, we identified Jam2 as necessary for the increased penetrance of Creld1-mediated septal defects in Ts65Dn. Thus, overexpression of the trisomic gene, Jam2, is a necessary potentiator of the disomic genetic modifier, Creld1. No direct physical interaction between Jam2 and Creld1 was identified by several methods. Regions of Hsa21 containing genes that are risk factors of CHD have been identified, but Jam2 (and its environs) has not been linked to heart formation previously. The complexity of this interaction may be more representative of the clinical situation in people than consideration of simple single-gene models.

[1]  Yufeng Shen,et al.  Increased Frequency of De Novo Copy Number Variants in Congenital Heart Disease by Integrative Analysis of Single Nucleotide Polymorphism Array and Exome Sequence Data , 2014, Circulation research.

[2]  J. Richtsmeier,et al.  Overlapping trisomies for human chromosome 21 orthologs produce similar effects on skull and brain morphology of Dp(16)1Yey and Ts65Dn mice , 2014, American journal of medical genetics. Part A.

[3]  P. Ye,et al.  Engineered chromosome-based genetic mapping establishes a 3.7 Mb critical genomic region for Down syndrome-associated heart defects in mice , 2014, Human Genetics.

[4]  M. Hoch,et al.  Murine Creld1 controls cardiac development through activation of calcineurin/NFATc1 signaling. , 2014, Developmental cell.

[5]  D. Linden,et al.  Hedgehog Agonist Therapy Corrects Structural and Cognitive Deficits in a Down Syndrome Mouse Model , 2013, Science Translational Medicine.

[6]  Xavier Estivill,et al.  The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome , 2013, Genome research.

[7]  C. Maslen,et al.  Genetic Modifiers Predisposing to Congenital Heart Disease in the Sensitized Down Syndrome Population , 2012, Circulation. Cardiovascular genetics.

[8]  Jef D. Boeke,et al.  Rapid Identification of Monospecific Monoclonal Antibodies Using a Human Proteome Microarray* , 2012, Molecular & Cellular Proteomics.

[9]  Gavin J. Wright,et al.  Jamb and Jamc Are Essential for Vertebrate Myocyte Fusion , 2011, PLoS biology.

[10]  Y. Hérault,et al.  Identification of the translocation breakpoints in the Ts65Dn and Ts1Cje mouse lines: relevance for modeling down syndrome , 2011, Mammalian Genome.

[11]  Yueming Ding,et al.  Molecular characterization of the translocation breakpoints in the Down syndrome mouse model Ts65Dn , 2011, Mammalian Genome.

[12]  Lora J. H. Bean,et al.  Variation in folate pathway genes contributes to risk of congenital heart defects among individuals with Down syndrome , 2010, Genetic epidemiology.

[13]  Lora J. H. Bean,et al.  Ethnicity, sex, and the incidence of congenital heart defects: a report from the National Down Syndrome Project , 2008, Genetics in Medicine.

[14]  Austin D. Williams,et al.  Characterization of the cardiac phenotype in neonatal Ts65Dn mice , 2008, Developmental dynamics : an official publication of the American Association of Anatomists.

[15]  E. Dejana,et al.  The role of junctional adhesion molecules in vascular inflammation , 2007, Nature Reviews Immunology.

[16]  Lora J. H. Bean,et al.  CRELD1 mutations contribute to the occurrence of cardiac atrioventricular septal defects in Down syndrome , 2006, American journal of medical genetics. Part A.

[17]  M. Kühl,et al.  The role of Wnt signalling in cardiac development and tissue remodelling in the mature heart. , 2006, Cardiovascular research.

[18]  C. S. Moore.  Postnatal lethality and cardiac anomalies in the Ts65Dn Down Syndrome mouse model , 2006, Mammalian Genome.

[19]  H. Kiyonari,et al.  Putative “Stemness” Gene Jam-B Is Not Required for Maintenance of Stem Cell State in Embryonic, Neural, or Hematopoietic Stem Cells , 2006, Molecular and Cellular Biology.

[20]  C. Maslen.  Molecular genetics of atrioventricular septal defects , 2004, Current opinion in cardiology.

[21]  C. Maslen,et al.  Missense mutations in CRELD1 are associated with cardiac atrioventricular septal defects. , 2003, American journal of human genetics.

[22]  R. Glanville,et al.  Identification, genomic organization and mRNA expression of CRELD1, the founding member of a unique family of matricellular proteins. , 2002, Gene.

[23]  R. Bjercke,et al.  A Novel Protein with Homology to the Junctional Adhesion Molecule , 2000, The Journal of Biological Chemistry.

[24]  J. Qian,et al.  Construction of human activity-based phosphorylation networks , 2013, Molecular systems biology.

[25]  D. Nižetić,et al.  Tumour angiogenesis is reduced in the Tc1 mouse model of Down’s syndrome , 2010, Nature.

[26]  M. Westerfield.  The zebrafish book : a guide for the laboratory use of zebrafish (Danio rerio) , 1995 .

[27]  J. McPherson,et al.  A Chromosome 21 Critical Region Does Not Cause Specific Down Syndrome Phenotypes , 2022 .