Human Molecular Genetics, 2001, Vol. 10, No. 2 163-169
© 2001 Oxford University Press
Familial Tetralogy of Fallot caused by mutation in the jagged1 gene
1Division of Cardiology, 2Institute of Genetic Medicine, 3Department of Surgery and 6Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA, 4Division of Pediatric Endocrinology, The University of Maryland Medical Center, Baltimore, MD, USA and 5Section of Thoracic and Cardiovascular Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
Tetralogy of Fallot (ToF) is the most common form of complex congenital heart disease, occurring in 
1 in 3000 live births. Evaluation of candidate loci in a large kindred segregating autosomal dominant ToF with reduced penetrance culminated in identification of a missense mutation (G274D) in JAG1, the gene encoding jagged1, a Notch ligand expressed in the developing right heart. Nine of eleven mutation carriers manifested cardiac disease, including classic ToF, ventricular septal defect with aortic dextroposition and isolated peripheral pulmonic stenosis (PPS). All forms of ToF were represented, including variants with pulmonic stenosis, pulmonic atresia and absent pulmonary valve. No individual within this family met diagnostic criteria for any previously described clinical syndrome, including Alagille syndrome (AGS), caused by haploinsufficiency for jagged1. All mutation carriers had characteristic but variable facial features, including long, narrow and upslanting palpebral fissures, prominent nasal bridge, square dental arch and broad, prominent chin. This appearance was distinct from that of unaffected family members and typical AGS patients. The glycine corresponding to position 274 is highly conserved in other epidermal growth factor-like domains of jagged1 and in those of other proteins. Its substitution in other proteins has been associated with mild or atypical variants of disease. These data support either a relative loss-of-function or a gain-of-function pathogenetic mechanism in this family and suggest that JAG1 mutations may contribute significantly to common variants of right heart obstructive disease.
+ To whom correspondence should be addressed at: Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Ross 858, 720 Rutland Avenue, Baltimore, MD 21287, USA. Tel: +1 410 614 0701; Fax: +1 410 614 2256; Email: hdietz@welch.jhu.edu
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  K. Niessen, Y. Fu, L. Chang, P. A. Hoodless, D. McFadden, and A. Karsan Slug is a direct Notch target required for initiation of cardiac cushion cellularization J. Cell Biol., July 28, 2008; 182(2): 315 - 325. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Piacentini, B. Marino, and M. C. Digilio Familial recurrence of discrete membranous subaortic stenosis J. Thorac. Cardiovasc. Surg., September 1, 2007; 134(3): 818 - 819. [Full Text] [PDF]
|
|
|
|
 |
|
 K. Niessen and A. Karsan Notch signaling in the developing cardiovascular system Am J Physiol Cell Physiol, July 1, 2007; 293(1): C1 - C11. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. E. Pierpont, C. T. Basson, D. W. Benson Jr, B. D. Gelb, T. M. Giglia, E. Goldmuntz, G. McGee, C. A. Sable, D. Srivastava, and C. L. Webb Genetic Basis for Congenital Heart Defects: Current Knowledge: A Scientific Statement From the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young: Endorsed by the American Academy of Pediatrics Circulation, June 12, 2007; 115(23): 3015 - 3038. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. Bashore Adult Congenital Heart Disease: Right Ventricular Outflow Tract Lesions Circulation, April 10, 2007; 115(14): 1933 - 1947. [Full Text] [PDF]
|
|
|
|
 |
|
 A. Fischer, C. Steidl, T. U. Wagner, E. Lang, P. M. Jakob, P. Friedl, K.-P. Knobeloch, and M. Gessler Combined Loss of Hey1 and HeyL Causes Congenital Heart Defects Because of Impaired Epithelial to Mesenchymal Transition Circ. Res., March 30, 2007; 100(6): 856 - 863. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. M.S. van den Akker, D. G.M. Molin, P. P.W.M. Peters, S. Maas, L. J. Wisse, R. van Brempt, C. J. van Munsteren, M. M. Bartelings, R. E. Poelmann, P. Carmeliet, et al. Tetralogy of Fallot and Alterations in Vascular Endothelial Growth Factor-A Signaling and Notch Signaling in Mouse Embryos Solely Expressing the VEGF120 Isoform Circ. Res., March 30, 2007; 100(6): 842 - 849. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Michielon, B. Marino, R. Formigari, G. Gargiulo, F. Picchio, M. C. Digilio, S. Anaclerio, G. Oricchio, S. P. Sanders, and R. M. Di Donato Genetic Syndromes and Outcome After Surgical Correction of Tetralogy of Fallot Ann. Thorac. Surg., March 1, 2006; 81(3): 968 - 975. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. B. Pauliks, K.-C. Chan, A. Lorts, E. R. Elias, R. O. Cayre, and L. M. Valdes-Cruz Shprintzen-Goldberg Syndrome With Tetralogy of Fallot and Subvalvar Aortic Stenosis J. Ultrasound Med., May 1, 2005; 24(5): 703 - 706. [Full Text] [PDF]
|
|
|
|
|
|
H. Kokubo, S. Miyagawa-Tomita, H. Tomimatsu, Y. Nakashima, M. Nakazawa, Y. Saga, and R. L. Johnson Targeted Disruption of hesr2 Results in Atrioventricular Valve Anomalies That Lead to Heart Dysfunction Circ. Res., September 3, 2004; 95(5): 540 - 547. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Noseda, G. McLean, K. Niessen, L. Chang, I. Pollet, R. Montpetit, R. Shahidi, K. Dorovini-Zis, L. Li, B. Beckstead, et al. Notch Activation Results in Phenotypic and Functional Changes Consistent With Endothelial-to-Mesenchymal Transformation Circ. Res., April 16, 2004; 94(7): 910 - 917. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Gruber and J. A. Epstein Development Gone Awry: Congenital Heart Disease Circ. Res., February 20, 2004; 94(3): 273 - 283. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B M Kamath, L Bason, D A Piccoli, I D Krantz, and N B Spinner Consequences of JAG1 mutations J. Med. Genet., December 1, 2003; 40(12): 891 - 895. [Abstract] [Full Text]
|
|
|
|
 |
|
 T. Gridley Notch signaling and inherited disease syndromes Hum. Mol. Genet., April 2, 2003; 12(90001): R9 - 13. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Slavotinek and L. G. Biesecker Genetic modifiers in human development and malformation syndromes, including chaperone proteins Hum. Mol. Genet., April 2, 2003; 12(90001): R45 - 50. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. McCright, J. Lozier, and T. Gridley A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency Development, March 4, 2003; 129(4): 1075 - 1082. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-E. Lin, T. Oyama, T. Nagase, K. Harigaya, and M. Kitagawa Identification of New Human Mastermind Proteins Defines a Family That Consists of Positive Regulators for Notch Signaling J. Biol. Chem., December 20, 2002; 277(52): 50612 - 50620. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. B. McElhinney, I. D. Krantz, L. Bason, D. A. Piccoli, K. M. Emerick, N. B. Spinner, and E. Goldmuntz Analysis of Cardiovascular Phenotype and Genotype-Phenotype Correlation in Individuals With a JAG1 Mutation and/or Alagille Syndrome Circulation, November 12, 2002; 106(20): 2567 - 2574. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A. Schroder, K. Tobita, J. P. Tinney, J. K. Foldes, and B. B. Keller Microtubule Involvement in the Adaptation to Altered Mechanical Load in Developing Chick Myocardium Circ. Res., August 23, 2002; 91(4): 353 - 359. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. E. Kiernan, N. Ahituv, H. Fuchs, R. Balling, K. B. Avraham, K. P. Steel, and M. H. de Angelis The Notch ligand Jagged1 is required for inner ear sensory development PNAS, March 16, 2001; (2001) 71496998. [Abstract] [Full Text]
|
|
|
|
|
|
A. E. Kiernan, N. Ahituv, H. Fuchs, R. Balling, K. B. Avraham, K. P. Steel, and M. Hrabe de Angelis The Notch ligand Jagged1 is required for inner ear sensory development PNAS, March 27, 2001; 98(7): 3873 - 3878. [Abstract] [Full Text] [PDF]
|
|