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      Apparently normal ovarian differentiation in a prepubertal girl with transcriptionally inactive steroidogenic factor 1 (NR5A1/SF-1) and adrenocortical insufficiency.

      American Journal of Human Genetics

      Adrenal Gland Diseases, genetics, metabolism, Amino Acid Sequence, Base Sequence, Child, Preschool, DNA, DNA-Binding Proteins, chemistry, Female, Fushi Tarazu Transcription Factors, Gene Expression Regulation, Genes, Reporter, Heterozygote, Homeodomain Proteins, Humans, Infant, Mutation, Missense, Ovary, growth & development, Phenotype, Protein Binding, Puberty, Receptors, Cytoplasmic and Nuclear, Steroidogenic Factor 1, Transcription Factors

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          Abstract

          Steroidogenic factor 1 (NR5A1/SF-1) plays an essential role in the development of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes, controlling expression of their many important genes. The recent description of a 46,XY patient bearing a mutation in the NR5A1 gene, causing male pseudohermaphroditism and adrenal failure, demonstrated the crucial role of SF-1 in male gonadal differentiation. The role of SF-1 in human ovarian development was, until now, unknown. We describe a phenotypically and genotypically normal girl, with signs and symptoms of adrenal insufficiency and no apparent defect in ovarian maturation, bearing a heterozygote G-->T transversion in exon 4 of the NR5A1 gene that leads to the missense R255L in the SF-1 protein. The exchange does not interfere with protein translation and stability. Consistent with the clinical picture, R255L is transcriptionally inactive and has no dominant-negative activity. The inability of the mutant (MUT) NR5A1/SF-1 to bind canonical DNA sequences might offer a possible explanation for the failure of the mutant protein to transactivate target genes. This is the first report of a mutation in the NR5A1 gene in a genotypically female patient, and it suggests that NR5A1/SF-1 is not necessary for female gonadal development, confirming the crucial role of NR5A1/SF-1 in adrenal gland formation in both sexes.

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          Journal
          11038323
          1287931
          10.1086/316893

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