Testicular differentiation factor SF-1 is required for human spleen development
David Zangen, … , Paul Renbaum, Ephrat Levy-Lahad
David Zangen, … , Paul Renbaum, Ephrat Levy-Lahad
Published April 8, 2014
Citation Information: J Clin Invest. 2014;124(5):2071-2075. https://doi.org/10.1172/JCI73186.
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Brief Report Genetics

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

Abstract

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.

Authors

David Zangen, Yotam Kaufman, Ehud Banne, Ariella Weinberg-Shukron, Abdulsalam Abulibdeh, Benjamin P. Garfinkel, Dima Dweik, Moein Kanaan, Núria Camats, Christa Flück, Paul Renbaum, Ephrat Levy-Lahad

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Figure 1

Phenotypic features of the patient.

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Phenotypic features of the patient. (A) CT scan of the patient’s abdomen...
(A) CT scan of the patient’s abdomen, revealing asplenia (arrow) and lack of uterus. (B) CT scan of the inguinal region, revealing inguinal testes (arrow). (C) Patient’s peripheral blood smear, with Howell-Jolly bodies (*), target cells (@), and poikilocytosis (#) indicative of asplenia. (D) H&E staining showed paucity of Leydig cells (arrow), lack of germinal cells, and abundance of Sertoli cells. (E) Paraffin-embedded sections of the patient’s testes immunostained with anti-inhibin antibody (brown). (F) Immunofluorescent staining of the proband’s testis with anti–SOX-9 antibody (green) and general nuclear staining with DAPI (red). Positive SOX-9 staining in Sertoli cells was similar in strength in the patient’s testes and in the control testes, which had a higher total number of cells, consisting mostly of germinal and pregerminal cells (not shown). Scale bars: 5 μm (C); 200 μm (D and E); 30 μm (F).