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Case Reports
. 2007 Dec;22(12):3255-61.
doi: 10.1093/humrep/dem278. Epub 2007 Oct 16.

Mutational analysis of steroidogenic factor 1 (NR5a1) in 24 boys with bilateral anorchia: a French collaborative study

Pascal Philibert  1 , Delphine Zenaty, Lin Lin, Sylvie Soskin, Françoise Audran, Juliane Léger, John C Achermann, Charles Sultan
Affiliations
Case Reports

Mutational analysis of steroidogenic factor 1 (NR5a1) in 24 boys with bilateral anorchia: a French collaborative study

Pascal Philibert et al. Hum Reprod. 2007 Dec.

Abstract

BACKGROUND Steroidogenic factor 1 (SF1/AdBP4/FTZF1, NR5A1) is a nuclear receptor transcription factor that plays a key role in regulating adrenal and gonadal development, steroidogenesis and reproduction. Recently, haploinsufficiency of SF1 has been described in several 46,XY individuals with mild gonadal dysgenesis and impaired androgenization, but normal adrenal function, suggesting that dosage-sensitive or domain-specific effects of SF1 action are important in human testicular development and function. Our objective was to investigate whether partial defects in SF1 function might be associated with milder male reproductive phenotypes, such as bilateral anorchia ('vanishing testis syndrome') and micropenis. METHODS This study involved mutational analysis of NR5A1 in 24 individuals with bilateral anorchia and micropenis from the French Collaborative Anorchia study, as well as in vitro functional studies of SF1-dependent transcriptional activation and computer modeling. RESULTS A novel heterozygous missense mutation (V355M) in SF1 was found in one boy with a micropenis and testicular regression syndrome. This non-synonymous change was found to affect a highly conserved amino acid within helix 7 of the ligand-binding domain of SF1. This V355M mutation did not affect stability or nuclear localization, but did result in an approximately 50% reduction in SF1 activity in several different assay systems. CONCLUSIONS In conclusion, heterozygous partial loss of function mutations in SF1 may be associated with bilateral anorchia ('vanishing testis syndrome') and micropenis in humans.

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Figures

Figure 1
Figure 1
(A) Genomic arrangement of the gene encoding SF1 (NR5A1) showing the G to A transversion in exon 6 (B) Cartoon of the structure of SF1 with the V355M mutation in the ligand-binding domain. (C) Chromatograph showing the heterozygous G to A transversion in the proband. (D) The mutated valine at position 355 lies within helix 7 and is highly conserved in homologues of SF1 from all species studied to date
Figure 2
Figure 2
Studies of SF1 expression and cellular localization GFP-SF1 fusion proteins (green) were created and expressed in tsa201 cells using a pAcGFP-C1 vector. Nuclear counterstaining was performed with DAPI (blue). Empty vector (−) showed diffuse localization throughout the cell cytoplasm and nucleus (upper panels). WT SF1 showed strong nuclear localization (center panels). A similar pattern of expression and localization to WT was seen following introduction of the V355M mutation (lower panels)
Figure 3
Figure 3
Transcriptional activation of SF1 _target gene promoters by WT and mutant V355M SF1 The activity of the G35E DNA-binding domain mutant associated with a more severe phenotype is shown for comparison. (A–D) Data for the MIS, Insl3, Cyp11a (scc) and Cyp19 minimal promoters in tsa 201 cells expressed as percentage of WT activity. (E and F) Data for the Cyp11a (scc) promoter in the TM3 Leydig cell line and CHO cells, respectively. (G) Mean transcriptional activation of WT and mutant SF1 for all six studies (A–F). (H) Activation of a UASTKluc promoter by GAL4-WT or V355M fusion proteins in tsa201 cells. Data represent the mean ± SEM of three independent experiments, each performed in triplicate
Figure 4
Figure 4
Predicted position of valine 355 within helix 7 of SF1 using recently published coordinates following crystallization of the SF1 ligand-binding domain (PDB; 1ZDT) Replacing this valine with a bulkier methionine residue would be expected to alter co-factor binding capacity of SF1
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