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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 Article has an altmetric score of 15

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

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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 2

Characterization of the SF1 mutation in the patient’s family.

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Characterization of the SF1 mutation in the patient’s family.
 
(A) Pedi...
(A) Pedigree of the patient’s consanguineous family. The proband (V1, arrow) a 46,XY female, has healthy first-cousin parents (IV1 and IV2) and 5 siblings (V2–V6). SF1 c.308 genotype (G, WT; A, mutant) is shown for each. (B) DNA sequencing chromatograms of the c.308G>A mutation (p.R103Q): homozygous in the proband, heterozygous in the mother, absent in a control (subject numbering as in A). (C) Cross-species conservation of the residues adjacent to R103 (dashed vertical outlines). Data were obtained from the UCSC human genome browser (24). (D) Conserved sequence of the Ftz-F1 box, the T-box and A-box subdomains, and the essential nuclear localization signal (Ess. NLS) of SF1 (6, 25). Residues mutated in the R92Q and R103Q mutations are denoted by single and double underline, respectively. (E) SF1 protein domains, including 2 zinc finger motifs, Ftz-F1 box (black box), proline-rich domain, hinge domain, and ligand-binding domain (LBD). (F) 3D model (generated using PyMol software; ref. 26) based on the solution structure of SF1 (7), showing the DNA-binding domain bound to its target sequence in the inhibin α subunit promoter. The 2 zinc finger motifs are shown in red, Ftz-F1 box is green, and R103 is blue. Inset shows the orientation of the R103 side chain, with the positive charge adjacent to the negatively charged DNA backbone.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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