Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic stenosis

Department of Pediatrics, The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104, USA.
Human Mutation (Impact Factor: 5.14). 05/2010; 31(5):594-601. DOI: 10.1002/humu.21231
Source: PubMed


Mutations in the Notch pathway ligand Jagged1 (JAG1) cause Alagille syndrome (AGS), as well as cardiac defects in seemingly nonsyndromic individuals. To estimate the frequency of JAG1 mutations in cases with right-sided cardiac defects not otherwise diagnosed with AGS, we screened 94 cases with tetralogy of Fallot (TOF) and 50 with pulmonic stenosis/peripheral pulmonary stenosis (PS/PPS) or pulmonary valve atresia with intact ventricular septum (PA) for mutations. Sequence changes were identified in three TOF and three PS/PPS/PA patients, that were not present in 100 controls. We identified one frameshift and two missense mutations in the TOF cases, and one frameshift and two missense mutations in cases with PS/PPS/PA. The four missense mutations were assayed for their effect on protein localization, posttranslational modification, and ability to activate Notch signaling. The missense mutants displayed heterogeneous behavior in these assays, some with complete haploinsufficiency, suggesting that there are additional modifiers leading to organ specific features. We identified functionally significant mutations in 2% (2/94) of TOF patients and 4% (2/50) of PS/PPS/PA patients. Patients with right-sided cardiac defects should be carefully screened for features of AGS or a family history of cardiac defects that might suggest the presence of a JAG1 mutation.

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    • "The retinoic acid receptors appear to be risk factors for the outflow tract, while TBX5 was identified as a risk target or responder gene for the outflow tract and atrial and ventricular septum [133]. The JAG1 genes which appeared in multiple datasets has previously been associated with TOF [134]. Finally this multidataset analysis revealed similar functional networks for CHD risk which include the NOTCH, BMP, TGF and PDGFR signaling pathway [133]. "
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    ABSTRACT: In many cases congenital heart disease (CHD) is represented by a complex phenotype and an array of several functional and morphological cardiac disorders. These malformations will be briefly summarized in the first part focusing on two severe CHD phenotypes, hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot (TOF). In most cases of CHD the genetic origin remains largely unknown, though the complexity of the clinical picture strongly argues against a dysregulation which can be attributed to a single candidate gene but rather suggests a multifaceted polygenetic origin with elaborate interactions. Consistent with this idea, genome-wide approaches using whole exome sequencing, comparative sequence analysis of multiplex families to identify de novo mutations and global technologies to identify single nucleotide polymorphisms, copy number variants, dysregulation of the transcriptome and epigenetic variations have been conducted to obtain information about genetic alterations and potential predispositions possibly linked to the occurrence of a CHD phenotype. In the second part of this review we will summarize and discuss the available literature on identified genetic alterations linked to TOF and HLHS.
    Full-text · Article · Apr 2015 · Current Genomics
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    • "A variety of gene insertion/deletion has been detected in patients with TOF. These genes include JAG1[10,11], NKX2-5 and GATA4[12,13] etc. However, a single gene mutation or deletion can be identified only in a small percentage of cases [14]. "
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    ABSTRACT: Although a lower methylation level of whole genome has been demonstrated in Tetralogy of Fallot (TOF) patients, little is known regarding changes in specific gene DNA methylation profiles and the possible associations with TOF. In current study, the promoter methylation statuses of congenital heart defect (CHD) candidate genes were measured in order to further understand epigenetic mechanisms that may play a role in the development of TOF. The methylation levels of CHD candidate genes were measured using the Sequenom MassARRAY platform. QRT-PCR was used to analyze the mRNA levels of CHD candidate genes in the right ventricular myocardium of TOF cases and normal controls. Methylation status analysis was performed on the promoter regions of 71 CHD candidate genes (113 amplicons). We found significant differences in methylation status, between TOF cases and controls, in 26 amplicons(26 genes)(p < 0.05). Of the 26 amplicons, 17 were up regulated and 9 were down regulated. Additionally, 14 of them were located in the CpG islands, 7 were located in the CpG island shores, and 5 were covering the regions near the transcription start site (TSS). The methylation status was subsequently confirmed and mRNA levels were measured for 7 represented candidate genes, including EGFR, EVC2, NFATC2, NR2F2, TBX5, CFC1B and GJA5. The methylation values of EGFR,EVC2, TBX5 and CFC1B were significantly correlated with their mRNA levels (p < 0.05). Aberrant promoter methylation statuses of CHD candidate genes presented in TOF cases may contribute to the TOF development and have potential prognostic and therapeutic significance for TOF disease.
    Full-text · Article · Jan 2014 · Journal of Translational Medicine
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    • "Among the CNVs detected in these 34 subjects, there were 16 subjects with 33 different CNVs involving 13 genes that are known to be critical for regulating development of the right ventricle making them good candidate genes for contributing to TOF (the genes were identified using the GO terms right ventricle morphogenesis or outflow track morphogenesis; Table 2). Two of these genes are known to be pathogenic, JAG1 [18], [29] and NOTCH1 [29], on chromosomes 9 and 20 respectively. Additionally, there were 79 genes from the list of 591 validated genes (genes that were experimentally determined to have a role in vertebrate heart development or function extracted from IPA) that were partially or completely contained in a CNV. "
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    ABSTRACT: Tetralogy of Fallot (TOF) is one of the most common severe congenital heart malformations. Great progress has been made in identifying key genes that regulate heart development, yet approximately 70% of TOF cases are sporadic and nonsyndromic with no known genetic cause. We created an ultra high-resolution gene centric comparative genomic hybridization (gcCGH) microarray based on 591 genes with a validated association with cardiovascular development or function. We used our gcCGH array to analyze the genomic structure of 34 infants with sporadic TOF without a deletion on chromosome 22q11.2 (n male = 20; n female = 14; age range of 2 to 10 months). Using our custom-made gcCGH microarray platform, we identified a total of 613 copy number variations (CNVs) ranging in size from 78 base pairs to 19.5 Mb. We identified 16 subjects with 33 CNVs that contained 13 different genes which are known to be directly associated with heart development. Additionally, there were 79 genes from the broader list of genes that were partially or completely contained in a CNV. All 34 individuals examined had at least one CNV involving these 79 genes. Furthermore, we had available whole genome exon arrays from right ventricular tissue in 13 of our subjects. We analyzed these for correlations between copy number and gene expression level. Surprisingly, we could detect only one clear association between CNVs and expression (GSTT1) for any of the 591 focal genes on the gcCGH array. The expression levels of GSTT1 were correlated with copy number in all cases examined (r = 0.95, p = 0.001). We identified a large number of small CNVs in genes with varying associations with heart development. Our results illustrate the complexity of human genome structural variation and underscore the need for multifactorial assessment of potential genetic/genomic factors that contribute to congenital heart defects.
    Full-text · Article · Jan 2014 · PLoS ONE
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