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

Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Filadelfia, Pennsylvania, United States
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
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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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    • "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.
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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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