• PMID: 21220346
• Gene Name: GATA4
• Condition: Testicular development, 46,XY DSD
• Association: 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 testiculardevelopment.
• Mutation: p.Gly221Arg
• Population size: 700
• Population details: 700 (250 newborns has some abnormality of genital and/or gonadal development, 450 ancestry-matched control individuals)
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Testicular development, 46,XY DSD

Loss-of-function mutation in GATA4 causes anomalies of human testicular development

Lourenço D, Brauner R, Rybczynska M, Nihoul-Fékété C, McElreavey K, Bashamboo A.

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-Müllerian 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. FAU - Lourenço, Diana AU - Lourenço D AD - Human Developmental Genetics, Institut Pasteur, 75724 Paris, France. FAU - Brauner, Raja AU - Brauner R FAU - Rybczynska, Magda AU - Rybczynska M FAU - Nihoul-Fékété, Claire AU - Nihoul-Fékété C FAU - McElreavey, Ken AU - McElreavey K