title: Loss-of-function mutation in GATA4 causes anomalies of human testicular development.
abstract: 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.
authors.affiliation: Human Developmental Genetics, Institut Pasteur, 75724 Paris, France.
authors.forename: Diana
authors.initials: D
authors.lastname: Lourenço
authors.forename: Raja
authors.initials: R
authors.lastname: Brauner
authors.forename: Magda
authors.initials: M
authors.lastname: Rybczynska
authors.forename: Claire
authors.initials: C
authors.lastname: Nihoul-Fékété
authors.forename: Ken
authors.initials: K
authors.lastname: McElreavey
authors.forename: Anu
authors.initials: A
authors.lastname: Bashamboo
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D002467:Cell Nucleus / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000378:metabolism; D012734:Disorders of Sex Development / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D005192:Family Health; D005260:Female; D005500:Follow-Up Studies; D050991:GATA4 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006330:Heart Defects, Congenital / Q000150:complications; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid; D054339:Steroidogenic Factor 1 / Q000378:metabolism; D013737:Testis / Q000002:abnormalities / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; C117427:ZFPM2 protein, human; D049452:Green Fluorescent Proteins