Loss-of-function mutation in <i>GATA4</i> causes anomalies of human testicular development
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- Diana Lourenço
- Human Developmental Genetics, Institut Pasteur, 75724 Paris, France;
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- Raja Brauner
- Faculté de Médecine and Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Unité d'Endocrinologie Pédiatrique, Hôpital Bicêtre, 94275 Le Kremlin Bicêtre, France; and
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- Magda Rybczyńska
- Human Developmental Genetics, Institut Pasteur, 75724 Paris, France;
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- Claire Nihoul-Fékété
- Faculté de Médecine and Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Hôpital Necker-Enfants Malades, Service de Chirurgie Viscérale Pédiatrique, 75743 Paris, France
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- Ken McElreavey
- Human Developmental Genetics, Institut Pasteur, 75724 Paris, France;
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- Anu Bashamboo
- Human Developmental Genetics, Institut Pasteur, 75724 Paris, France;
書誌事項
- 公開日
- 2011-01-10
- DOI
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- 10.1073/pnas.1010257108
- 公開者
- Proceedings of the National Academy of Sciences
この論文をさがす
説明
<jats:p> 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 <jats:italic>GATA4</jats:italic> 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-Müllerian hormone ( <jats:italic>AMH</jats:italic> ) promoter. The mutation does not interfere with the direct protein–protein interaction, but it disrupts synergistic activation of the <jats:italic>AMH</jats:italic> 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. </jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 108 (4), 1597-1602, 2011-01-10
Proceedings of the National Academy of Sciences