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Jagged1 ( JAG1 ) mutations in patients with tetralogy of fallot or pulmonic stenosis
Author(s) -
Bauer Robert C.,
Laney Ayanna O.,
Smith Rosemarie,
Gerfen Jennifer,
Morrissette Jennifer J.D.,
Woyciechowski Stacy,
Garbarini Jennifer,
Loomes Kathleen M.,
Krantz Ian D.,
Urban Zsolt,
Gelb Bruce D.,
Goldmuntz Elizabeth,
Spinner Nancy B.
Publication year - 2010
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21231
Subject(s) - jag1 , missense mutation , frameshift mutation , haploinsufficiency , pulmonic stenosis , tetralogy of fallot , biology , alagille syndrome , pulmonary atresia , mutation , pulmonary valve stenosis , genetics , medicine , stenosis , cardiology , notch signaling pathway , endocrinology , pulmonary artery , heart disease , phenotype , signal transduction , gene , cholestasis
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. Hum Mutat 31:594–601, 2010. © 2010 Wiley‐Liss, Inc.