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Hum. Reprod. Advance Access published online on October 16, 2007
Human Reproduction, doi:10.1093/humrep/dem278
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© The Author 2007. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Pascal Philibert1, Delphine Zenaty2, Lin Lin3, Sylvie Soskin4, Françoise Audran1, Juliane Léger2, John C. Achermann3 and Charles Sultan1,5,6

1 Service d’Hormonologie, Hôpital Lapeyronie, CHU Montpellier, 34295 Montpellier cedex 5, France 2 Service d’Endocrinologie Pédiatrique, Hôpital Robert Debré, AP-HP, 75935 Paris, France 3 Developmental Endocrinology Research Group, Clinical and Molecular Genetics, UCL Institute of Child Health, University College London, London WC1N 1EH, UK 4 Service de Pédiatrie I, Unité d’Endocrinologie, Hôpitaux Universitaires de Strasbourg, 67200 Strasbourg, France 5 Unité d’Endocrinologie Pédiatrique (C.S.), Hôpital Arnaud de Villeneuve, CHU Montpellier, 34295 Montpellier, France

6Correspondence address. Tel: +33-467-33-86-96; Fax: +33-467-04-85-73; E-mail: c-sultan{at}chu-montpellier.fr

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 ~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.

Key words: SF1/gonadal dysgenesis/vanishing testis syndrome/testicular regression/disorders of sexual development

{dagger} Partially presented at the 45th ESPE Annual Meeting, Rotterdam, 2006. Abstract in Horm Res 2006;65(Suppl 4):110–111.

Submitted on May 8, 2007; resubmitted on June 13, 2007; accepted on June 18, 2007.


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