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Conditional JAG1 mutation shows the developing heart is more sensitive than developing liver to JAG1 dosage.
Fengmin Lu1, Jennifer J D Morrissette, Nancy B Spinner
1Division of Human Genetics and Molecular Biology, Department of Pediatrics and Clinical Laboratories, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
American Journal of Human Genetics
|March 22, 2003
Summary
Mutations in Jagged 1 (JAG1) cause Alagille syndrome. A specific JAG1 mutation leads to cardiac defects by producing less functional JAG1 protein, showing temperature sensitivity and impacting heart development more than liver development.
Area of Science:
- Genetics
- Developmental Biology
- Molecular Medicine
Background:
- Alagille syndrome (AGS) is an autosomal dominant disorder caused by Jagged 1 (JAG1) mutations, typically involving bile duct paucity and other systemic features.
- Haploinsufficiency of JAG1 is the presumed mechanism for AGS, with limited genotype-phenotype correlations observed.
- A specific JAG1 missense mutation, JAG1-G274D, was identified in families with cardiac defects but without liver disease.
Purpose of the Study:
- To investigate the molecular mechanism of the JAG1-G274D missense mutation.
- To understand why this mutation leads to cardiac defects without liver involvement in Alagille syndrome.
- To explore the functional consequences of the JAG1-G274D mutation on protein transport and Notch signaling.
Main Methods:
- Analysis of JAG1 protein production and intracellular trafficking in cells with the JAG1-G274D mutation.
- Assessment of cell surface JAG1 levels and Notch signaling activity.
- Evaluation of the temperature sensitivity of the JAG1-G274D protein.
Main Results:
- The JAG1-G274D mutation results in two protein populations: one abnormally glycosylated and intracellularly retained, the other normally glycosylated and cell surface-expressed.
- The JAG1-G274D protein exhibits temperature sensitivity, with increased misfolded protein at higher temperatures.
- Individuals with the JAG1-G274D mutation have reduced cell surface JAG1 levels (>50% but <100% of normal).
Conclusions:
- The JAG1-G274D mutation is a 'leaky' mutation, causing a partial loss of functional JAG1 protein.
- The cardiac-specific phenotype suggests differential sensitivity of developing organs to JAG1 dosage, with the heart being more susceptible to reduced JAG1 levels.
- This study highlights the complex relationship between JAG1 mutations, protein function, and the manifestation of Alagille syndrome phenotypes.