NOTCH2 Mutations Cause Alagille Syndrome, a Heterogeneous Disorder of the Notch Signaling Pathway

Division of Human Genetics and Molecular Biology, The Children's Hospital of Philadelphia, PA 19104, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 08/2006; 79(1):169-73. DOI: 10.1086/505332
Source: PubMed


Alagille syndrome (AGS) is caused by mutations in the gene for the Notch signaling pathway ligand Jagged1 (JAG1), which are found in 94% of patients. To identify the cause of disease in patients without JAG1 mutations, we screened 11 JAG1 mutation-negative probands with AGS for alterations in the gene for the Notch2 receptor (NOTCH2). We found NOTCH2 mutations segregating in two families and identified five affected individuals. Renal manifestations, a minor feature in AGS, were present in all the affected individuals. This demonstrates that AGS is a heterogeneous disorder and implicates NOTCH2 mutations in human disease.

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Available from: Ryan Mcdaniell, Sep 29, 2015
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    • ". Therefore, it is not surprising to find mutations in JAGGED1 in Alagille syndrome [55]. NOTCH2 mutations have also been found in Alagille syndrome patients [56]. Mutations in the genes responsible for the cell regulatory mechanisms, Ras/MAPK pathway could also cause a variety of syndromes, including Noonan syndrome (NS) and its variant Leopard syndrome (LS). "
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    ABSTRACT: Congenital heart defect (CHD) has a major influence on affected individuals as well as the supportive and associated environment such as the immediate family. Unfortunately, CHD is common worldwide with an incidence of approximately 1% and consequently is a major health concern. The Arab population has a high rate of consanguinity, fertility, birth and annual population growth, in addition to a high incidence of diabetes mellitus and obesity. All these factors may lead to a higher incidence and prevalence of CHD within the Arab population than in the rest of the world making CHD of even greater concern. Sadly, most Arab countries lack appropriate public health measures directed toward the control and prevention of congenital malformations and so the importance of CHD within the population remains unknown but is thought to be high. In approximately 85% of CHD patients, the multifactorial theory is considered as the pathologic basis. The genetic risk factors for CHD can be attributed to large chromosomal aberrations, copy number variations (CNV) of particular regions in the chromosome, gene mutations in specific nuclear transcription pathways, and also in the genes that are involved in cardiac structure and development. The application of modern molecular biology techniques such as high throughput nucleotide sequencing and chromosomal array, and methylation array all have the potential to reveal more genetic defects linked to CHD. Exploring the genetic defects in CHD pathology will improve our knowledge and understanding about the diverse pathways involved and also about the progression of this disease. Ultimately, this will link to more efficient genetic diagnosis and development of novel preventive therapeutic strategies, as well as gene-targeted clinical management. This review summarizes our current understanding of the molecular basis of normal heart development and the pathophysiology of a wide range of CHD. The risk factors that might account for the high prevalence of CHD within the Arab population and the measures required to be undertaken for conducting research into CHD in Arab countries will also be discussed.
    Trends in Cardiovascular Medicine 11/2014; 25(4). DOI:10.1016/j.tcm.2014.11.007 · 2.91 Impact Factor
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    • "In patients negative for JAG1 point mutations, MLPA screening for large deletions involving JAG1 gene should be executed. The JAG1 gene analysis might be completed by the NOTCH2 gene screening, however the analysis of this gene seems to be of minor importance in the ALGS routine diagnostics as NOTCH2 mutations have been reported so far only in ten patients with ALGS features (McDaniell et al. 2006; Kamath et al. 2012). The proposed strategy is based on methods commonly available in most laboratories, primarily Sanger sequencing. "
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    ABSTRACT: Alagille syndrome (ALGS) is an autosomal dominant disorder characterized by developmental abnormalities in several organs including the liver, heart, eyes, vertebrae, kidneys, and face. The majority (90-94 %) of ALGS cases are caused by mutations in the JAG1 (JAGGED1) gene, and in a small percent of patients (∼1 %) mutations in the NOTCH2 gene have been described. Both genes are involved in the Notch signaling pathway. To date, over 440 different JAG1 gene mutations and ten NOTCH2 mutations have been identified in ALGS patients. The present study was conducted on a group of 35 Polish ALGS patients and revealed JAG1 gene mutations in 26 of them. Twenty-three different mutations were detected including 13 novel point mutations and six large deletions affecting the JAG1 gene. Review of all mutations identified to date in individuals from Poland allowed us to propose an effective diagnostic strategy based on the mutations identified in the reported patients of Polish descent. However, the distribution of mutations seen in this cohort was not substantively different than the mutation distribution in other reported populations.
    Journal of applied genetics 04/2014; 55(3). DOI:10.1007/s13353-014-0212-2 · 1.48 Impact Factor
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    • "Genome sequencing analyses did not reveal recurrent mutations in Notch pathway genes in hepatocellular carcinoma (HCC), a leading cause of cancer-related deaths worldwide (Fujimoto et al., 2012; Guichard et al., 2012). Nevertheless, Notch signaling has been of interest to liver cancer biologists because of the prominent role of Notch signaling in liver development, including mutations in NOTCH2 or JAG1 in patients with Alagille syndrome (syndromic bile duct paucity) (McDaniell et al., 2006; Oda et al., 1997). Haploinsufficient mutations in a specific ligand and a specific receptor in the Notch pathway would suggest that Notch signaling could play very context-and level-dependent roles in liver tumors. "
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    ABSTRACT: Since Notch phenotypes in Drosophila melanogaster were first identified 100 years ago, Notch signaling has been extensively characterized as a regulator of cell-fate decisions in a variety of organisms and tissues. However, in the past 20 years, accumulating evidence has linked alterations in the Notch pathway to tumorigenesis. In this review, we discuss the protumorigenic and tumor-suppressive functions of Notch signaling, and dissect the molecular mechanisms that underlie these functions in hematopoietic cancers and solid tumors. Finally, we link these mechanisms and observations to possible therapeutic strategies targeting the Notch pathway in human cancers.
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