ALGS. More recently JAG1 expression has been found to be altered in breast cancer and adrenocortical carcinoma patients. Mouse models where the Jag1 gene is turned off in certain tissues (conditional knockout mouse models) have been used to study the role of Jag1 in many tissue specific areas. While homozygous deletions of Jag1 have been shown to be embryonic lethal in mice, and heterozygous deletions may show only a limited phenotype (involving the eye), mice haploinsufficient for both Jag1 and Notch2 present with the ALGS phenotype. Conditional gene knockout mouse models with Jag1 mutations targeted to the portal vein mesenchyme, endothelium, and cranial neural crest all exhibit features classic to those in individuals with ALGS, highlighting the role of this tissue type in disease origins Disease phenotype ALGS is an autosomal dominant multi-system disorder affecting several body systems including the liver, heart, skeleton, eye, facial structure, kidneys and vascular system. The most clinically significant concerns stem from liver, heart, vascular or renal problems. Mutations in JAG1 were first discovered to be responsible for ALGS by researchers at The Children's Hospital of Philadelphia and the National Institutes of Health in 1997. Patients who are clinically consistent with the disorder usually have a mutation in JAG1 (94%), while a smaller 2% have a mutation in NOTCH2. Over half of individuals with mutations in the gene did not inherit it from either parent, and thus have a de novo mutation. JAG1 mutation types include protein truncating (splice site, frameshift, and nonsense), missense, and whole gene deletions accounting for 80%, 7%, and 12% respectively. Since all mutation types lead to a patient phenotype, it is thought that haploinsufficiency for JAG1 is the likely disease mechanism of action. Although individuals can have a range of mutation types in JAG1, all of the known mutations lead to loss of the function of one copy, and, there is no correlation between mutation type or location and disease severity. Though individuals with ALGS have several body systems affected, there is a subset of individuals with JAG1 mutations who present with tetralogy of fallot/pulmonary stenosis that do not show the other clinical signs of the syndrome. Given the variable expressivity of the disease, there may be other genetic or environmental modifiers present beyond the original JAG1 mutation. More recently, JAG1 expression changes have been implicated in many types of cancer. Specifically, up regulation of JAG1 has been correlated with