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Conditional JAG1 mutation shows the developing heart is more sensitive than developing liver to JAG1 dosage.
- Source :
-
American journal of human genetics [Am J Hum Genet] 2003 Apr; Vol. 72 (4), pp. 1065-70. Date of Electronic Publication: 2003 Mar 14. - Publication Year :
- 2003
-
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.
- Subjects :
- Amino Acid Substitution
Calcium-Binding Proteins
Gene Expression Regulation, Developmental
Genes, Dominant
Genetic Carrier Screening
Humans
Intercellular Signaling Peptides and Proteins
Jagged-1 Protein
Membrane Proteins
Mutation, Missense
Organ Specificity
Serrate-Jagged Proteins
Alagille Syndrome genetics
Gene Dosage
Heart embryology
Liver embryology
Mutation
Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0002-9297
- Volume :
- 72
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- American journal of human genetics
- Publication Type :
- Academic Journal
- Accession number :
- 12649809
- Full Text :
- https://doi.org/10.1086/374386