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Testicular differentiation factor SF-1 is required for human spleen development

2014; American Society for Clinical Investigation; Volume: 124; Issue: 5 Linguagem: Inglês

10.1172/jci73186

1558-8238

David Zangen, Yotam Kaufman, Ehud Banne, Ariella Weinberg‐Shukron, Abdulsalam Abu‐Libdeh, Benjamin P. Garfinkel, Dima Dweik, Moien Kanaan, Núria Camats, Christa E. Flück, Paul Renbaum, Ephrat Levy‐Lahad,

Sperm and Testicular Function

The transcription factor steroidogenic factor 1 (SF-1; also known as NR5A1) is a crucial mediator of both steroidogenic and nonsteroidogenic tissue differentiation. Mutations within SF1 underlie different disorders of sexual development (DSD), including sex reversal, spermatogenic failure, ovarian insufficiency, and adrenocortical deficiency. Here, we identified a recessive mutation within SF1 that resulted in a substitution of arginine to glutamine at codon 103 (R103Q) in a child with both severe 46,XY-DSD and asplenia. The R103Q mutation decreased SF-1 transactivation of TLX1, a transcription factor that has been shown to be essential for murine spleen development. Additionally, the SF1 R103Q mutation impaired activation of steroidogenic genes, without affecting synergistic SF-1 and sex-determining region Y (SRY) coactivation of the testis development gene SOX9. Together, our data provide evidence that SF-1 is required for spleen development in humans via transactivation of TLX1 and that mutations that only impair steroidogenesis, without altering the SF1/SRY transactivation of SOX9, can lead to 46,XY-DSD.