ArticleAmerican journal of human genetics2003
Conditional JAG1 mutation shows the developing heart is more sensitive than developing liver to JAG1 dosage.
Article in American journal of human genetics, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 57 citations in OpenAlex.
- Likelihood-based calibration improves the clinical utility of JAG1 functional data for variant classification.American journal of human genetics · 2026Article
- Functional characterization of 2,832 JAG1 variants supports reclassification for Alagille syndrome and improves guidance for clinical variant interpretation.American journal of human genetics · 2024Article
- Alagille syndrome and non-syndromic paucity of the intrahepatic bile ducts.Translational gastroenterology and hepatology · 2021Review
- Peritoneal dialysis in an adult patient with tetralogy of Fallot diagnosed with incomplete Alagille syndrome.BMC medical genetics · 2020Article
- Genetic Basis of Human Congenital Heart Disease.Cold Spring Harbor perspectives in biology · 2020Article
- Alagille syndrome mutation update: Comprehensive overview of JAG1 and NOTCH2 mutation frequencies and insight into missense variant classification.Human mutation · 2019Article
- Genetic Basis for Congenital Heart Disease: Revisited: A Scientific Statement From the American Heart Association.Circulation · 2018Review
- Human hepatic organoids for the analysis of human genetic diseases.JCI insight · 2017Article
- Alagille syndrome: Genetics and Functional Models.Current pathobiology reports · 2017Article
- The NOTCH Ligand JAG1 Regulates GDNF Expression in Sertoli Cells.Stem cells and development · 2017Article
- Mutations in POFUT1, encoding protein O-fucosyltransferase 1, cause generalized Dowling-Degos disease.American journal of human genetics · 2013Article
- Alagille Syndrome: A New Missense Mutation Detected by Whole-Exome Sequencing in a Case Previously Found to Be Negative by DHPLC and MLPA.Molecular syndromology · 2013Article
- Article
- Notch signaling in human development and disease.Seminars in cell & developmental biology · 2012Review
- Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic stenosis.Human mutation · 2010Article
- The contribution of Notch1 to nephron segmentation in the developing kidney is revealed in a sensitized Notch2 background and can be augmented by reducing Mint dosage.Developmental biology · 2010Article
- Structure-function analysis of delta trafficking, receptor binding and signaling in Drosophila.Genetics · 2006Article
- Expression of mutant JAGGED1 alleles in patients with Alagille syndrome.Human genetics · 2005Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Mutations of Jagged 1 (JAG1), a ligand in the Notch signaling pathway, cause Alagille syndrome (AGS). AGS is an autosomal dominant, multisystem disorder with variable expressivity, characterized by bile duct paucity and resultant liver disease in combination with cardiac, ocular, skeletal, and facial findings. JAG1 mutations in AGS include gene deletions and protein truncating, splicing, and missense mutations, suggesting that haploinsufficiency is the mechanism of disease causation. With limited exceptions, there is no genotype-phenotype correlation. We have studied a JAG1 missense mutation (JAG1-G274D) that was previously identified in 13 individuals from an extended family with cardiac defects of the type seen in patients with AGS (e.g., peripheral pulmonic stenosis and tetralogy of Fallot) in the absence of liver dysfunction. Our data indicate that this mutation is "leaky." Two populations of proteins are produced from this allele. One population is abnormally glycosylated and is retained intracellularly rather than being transported to the cell surface. A second population is normally glycosylated and is transported to the cell surface, where it is able to signal to the Notch receptor. The JAG1-G274D protein is temperature sensitive, with more abnormally glycosylated (and nonfunctional) molecules produced at higher temperatures. Carriers of this mutation therefore have >50% but <100% of the normal concentration of JAG1 molecules on the cell surface. The cardiac-specific phenotype associated with this mutation suggests that the developing heart is more sensitive than the developing liver to decreased dosage of JAG1.
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