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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.

Pubmed ID: 20437614

Authors

  • Bauer RC
  • Laney AO
  • Smith R
  • Gerfen J
  • Morrissette JJ
  • Woyciechowski S
  • Garbarini J
  • Loomes KM
  • Krantz ID
  • Urban Z
  • Gelb BD
  • Goldmuntz E
  • Spinner NB

Journal

Human mutation

Publication Data

May 3, 2010

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK53104
  • Agency: NCRR NIH HHS, Id: M01 RR000240-42
  • Agency: NCRR NIH HHS, Id: M01-RR-000240
  • Agency: NHLBI NIH HHS, Id: P50 HL074731
  • Agency: NHLBI NIH HHS, Id: P50 HL074731-02
  • Agency: NHLBI NIH HHS, Id: P50 HL62177-05
  • Agency: NHLBI NIH HHS, Id: P50 HL74731
  • Agency: NIDDK NIH HHS, Id: R01 DK053104
  • Agency: NIDDK NIH HHS, Id: R01 DK053104-09S1
  • Agency: NIDDK NIH HHS, Id: R01 DK081702
  • Agency: NCRR NIH HHS, Id: UL1 RR024134
  • Agency: NCRR NIH HHS, Id: UL1 RR024134-04
  • Agency: NCRR NIH HHS, Id: UL1-RR-024134

Mesh Terms

  • Alagille Syndrome
  • Animals
  • Calcium-Binding Proteins
  • DNA Mutational Analysis
  • Female
  • Glycosylation
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Male
  • Membrane Proteins
  • Mice
  • Mutation
  • Mutation, Missense
  • NIH 3T3 Cells
  • Pedigree
  • Protein Processing, Post-Translational
  • Pulmonary Valve Stenosis
  • Signal Transduction
  • Tetralogy of Fallot