Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 4, Pages 1597-1602Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1010257108
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Funding
- Laboratoire Lilly France
- Agence Nationale de la Recherche-GIS Institut des Maladies Rares
- March of Dimes Foundation [1-FY07-490]
- European Community [201444]
- Portuguese Foundation for Science and Technology
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Approximately 1 of every 250 newborns has some abnormality of genital and/or gonadal development. However, a specific molecular cause is identified in only 20% of these cases of disorder of sex development (DSD). We identified a family of French origin presenting with 46, XY DSD and congenital heart disease. Sequencing of the ORF of GATA4 identified a heterozygous missense mutation (p.Gly221Arg) in the conserved N-terminal zinc finger of GATA4. This mutation was not observed in 450 ancestry-matched control individuals. The mutation compromised the ability of the protein to bind to and transactivate the anti-Mullerian hormone (AMH) promoter. The mutation does not interfere with the direct protein-protein interaction, but it disrupts synergistic activation of the AMH promoter by GATA4 and NR5A1. The p.Gly221Arg mutant protein also failed to bind to a known protein partner FOG2 that is essential for gonad formation. Our data demonstrate the key role of GATA4 in human testicular development.
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