Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic stenosis.
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.
Bauer
Robert C
RC
Department of Pediatrics, The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104, USA.
Laney
Ayanna O
AO
Smith
Rosemarie
R
Gerfen
Jennifer
J
Morrissette
Jennifer J D
JJ
Woyciechowski
Stacy
S
Garbarini
Jennifer
J
Loomes
Kathleen M
KM
Krantz
Ian D
ID
Urban
Zsolt
Z
Gelb
Bruce D
BD
Goldmuntz
Elizabeth
E
Spinner
Nancy B
NB
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*
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