title: Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic stenosis.
abstract: Mutations in the Notch pathway ligand Jagged1 (JAG1) cause Alagille syndrome (AGS), as well as cardiac defects in seemingly nonsyndromic individuals. To estimate the frequency of JAG1 mutations in cases with right-sided cardiac defects not otherwise diagnosed with AGS, we screened 94 cases with tetralogy of Fallot (TOF) and 50 with pulmonic stenosis/peripheral pulmonary stenosis (PS/PPS) or pulmonary valve atresia with intact ventricular septum (PA) for mutations. Sequence changes were identified in three TOF and three PS/PPS/PA patients, that were not present in 100 controls. We identified one frameshift and two missense mutations in the TOF cases, and one frameshift and two missense mutations in cases with PS/PPS/PA. The four missense mutations were assayed for their effect on protein localization, posttranslational modification, and ability to activate Notch signaling. The missense mutants displayed heterogeneous behavior in these assays, some with complete haploinsufficiency, suggesting that there are additional modifiers leading to organ specific features. We identified functionally significant mutations in 2% (2/94) of TOF patients and 4% (2/50) of PS/PPS/PA patients. Patients with right-sided cardiac defects should be carefully screened for features of AGS or a family history of cardiac defects that might suggest the presence of a JAG1 mutation.
authors.affiliation: Department of Pediatrics, The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Bauer
authors.forename: Ayanna O
authors.initials: AO
authors.lastname: Laney
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Smith
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gerfen
authors.forename: Jennifer J D
authors.initials: JJ
authors.lastname: Morrissette
authors.forename: Stacy
authors.initials: S
authors.lastname: Woyciechowski
authors.forename: Jennifer
authors.initials: J
authors.lastname: Garbarini
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Loomes
authors.forename: Ian D
authors.initials: ID
authors.lastname: Krantz
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Urban
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gelb
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Goldmuntz
authors.forename: Nancy B
authors.initials: NB
authors.lastname: Spinner
mesh_terms: D016738:Alagille Syndrome / Q000235:genetics; D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D004252:DNA Mutational Analysis; D005260:Female; D006031:Glycosylation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D020125:Mutation, Missense; D041681:NIH 3T3 Cells; D010375:Pedigree; D011499:Protein Processing, Post-Translational; D011666:Pulmonary Valve Stenosis / Q000235:genetics*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000235:genetics; D013771:Tetralogy of Fallot / Q000235:genetics*
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D000072099:Serrate-Jagged Proteins