Conditional JAG1 Mutation Shows the Developing Heart Is More Sensitive Than Developing Liver to JAG1 Dosage

• Published in: American journal of human genetics Vol. 72; no. 4; pp. 1065 - 1070
• Main Authors: Lu, Fengmin, Jennifer Morrissette, J.D., Spinner, Nancy B.
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.04.2003; University of Chicago Press; The American Society of Human Genetics
• Subjects: Alagille Syndrome - genetics; Amino Acid Substitution; Biological and medical sciences; Calcium-Binding Proteins; Cardiology. Vascular system; Congenital heart diseases. Malformations of the aorta, pulmonary vessels and vena cava; Gene Dosage; Gene Expression Regulation, Developmental; Genes, Dominant; Genetic Carrier Screening; Heart; Heart - embryology; Humans; Intercellular Signaling Peptides and Proteins; Jagged-1 Protein; Liver - embryology; Medical sciences; Membrane Proteins; Mutation; Mutation, Missense; Organ Specificity; Proteins - genetics; Serrate-Jagged Proteins; Heart; Human; Gene dosage; Embryonic development; Congenital; Family study; Pathogenesis; Alagille syndrome; Liver; Cardiovascular disease; Hepatic disease; Genotype; Congenital disease; Genetic determinism; Genetic disease; Phenotype; Missense mutation; Gene; Autosomal character; Heart disease; Digestive diseases; Dominant character; Complex syndrome
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/374386

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.