title: Oxidative stress-induced apoptosis in two patients with Alagille syndrome.
abstract: Alagille syndrome (AGS) is an autosomal dominant disorder characterized by cholestasis, cardiac, skeletal and ocular abnormalities. Increasing importance is being given to vascular and central nervous system impairment. AGS is in most cases caused by heterozygous mutations in the Jagged-1 (JAG1) gene encoding a cell-surface ligand of the Notch receptors. The interaction between Notch1 and JAG1 induces proliferation and inhibits apoptosis. We evaluated the role of apoptosis in AGS patients carrying a truncating mutation in exon 7 of JAG1. Peripheral blood lymphocytes (PBLs) from two patients were exposed to 2-deoxy-d-ribose (dRib). Apoptosis was analyzed by flow cytometry, fluorescence microscopy and Western blotting. PBLs from patients showed a significantly higher percentage of apoptosis than controls both in standard culture conditions and after dRib treatment, however we demonstrated a lack of caspase-8 activation in those cells. Our results confirm that JAG1 may play a role in apoptosis regulation. In particular, truncating mutations in JAG1 could lead to Notch signaling inhibition and determine a deregulation of survival and proliferation, favoring apoptosis. Moreover, the lack of caspase-8 activation in AGS patients indicates a possible selective impairment of caspase-8 cleavage suggesting that JAG1 plays a specific role in the regulation of caspase-8 activation.
authors.affiliation: Department of Neurological, Neurosurgical and Behavioural Sciences, University of Siena, Siena, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Radi
authors.forename: Patrizia
authors.initials: P
authors.lastname: Formichi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Maio
authors.forename: Carla
authors.initials: C
authors.lastname: Battisti
authors.forename: Antonio
authors.initials: A
authors.lastname: Federico
mesh_terms: D000328:Adult; D016738:Alagille Syndrome / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D005260:Female; D017353:Gene Deletion; D006580:Genetic Carrier Screening; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D000072099:Serrate-Jagged Proteins
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; D000072099:Serrate-Jagged Proteins