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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 4; pp. 1597 - 1602
• Main Authors: Lourenço, Diana, Brauner, Raja, Rybczyńska, Magda, Nihoul-Fékété, Claire, McElreavey, Ken, Bashamboo, Anu
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 25.01.2011; National Acad Sciences
• Subjects: Adolescent; Amino Acid Sequence; Binding sites; Biochemistry; Biological Sciences; Cardiovascular disease; Cardiovascular diseases; Cell Nucleus - metabolism; Child; Child, Preschool; Congenital heart defects; Disorders of Sex Development - complications; Disorders of Sex Development - genetics; Disorders of Sex Development - metabolism; DNA; DNA Mutational Analysis; DNA-Binding Proteins - metabolism; Family Health; Female; Follow-Up Studies; GATA transcription factors; GATA4 Transcription Factor - genetics; GATA4 Transcription Factor - metabolism; Genealogy; Genes; Genetic mutation; Genetic vectors; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Heart Defects, Congenital - complications; heart diseases; HEK293 Cells; heterozygosity; Hormones; Human subjects; Humans; Infant, Newborn; loss-of-function mutation; Male; missense mutation; Molecular Sequence Data; mutants; Mutation; neonates; open reading frames; Pedigree; Protein Binding; protein-protein interactions; Proteins; Sequence Homology, Amino Acid; Steroidogenic Factor 1 - metabolism; Testes; Testicular development; Testis - abnormalities; Testis - metabolism; Transcription factors; Transcription Factors - metabolism; Urogenital system; Zinc; zinc finger motif
• DOI: 10.1073/pnas.1010257108
• ISSN: 0027-8424; 1091-6490

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.