Mutational analysis of steroidogenic factor 1 (NR5a1) in 24 boys with bilateral anorchia: a French collaborative study
- 16 October 2007
- journal article
- case report
- Published by Oxford University Press (OUP) in Human Reproduction
- Vol. 22 (12), 3255-3261
- https://doi.org/10.1093/humrep/dem278
Abstract
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. 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. 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. In conclusion, heterozygous partial loss of function mutations in SF1 may be associated with bilateral anorchia (‘vanishing testis syndrome’) and micropenis in humans.Keywords
This publication has 43 references indexed in Scilit:
- Heterozygous Mutation of Steroidogenic Factor-1 in 46,XY Subjects May Mimic Partial Androgen Insensitivity SyndromeJournal of Clinical Endocrinology & Metabolism, 2007
- Gonadal Dysgenesis Without Adrenal Insufficiency in a 46, XY Patient Heterozygous for the Nonsense C16X Mutation: A Case of SF1 HaploinsufficiencyJournal of Clinical Endocrinology & Metabolism, 2004
- Cell-Specific Knockout of Steroidogenic Factor 1 Reveals Its Essential Roles in Gonadal FunctionMolecular Endocrinology, 2004
- A Microdeletion in the Ligand Binding Domain of Human Steroidogenic Factor 1 Causes XY Sex Reversal without Adrenal InsufficiencyJournal of Clinical Endocrinology & Metabolism, 2004
- Discordance of Monozygotic Twins for Thyroid Dysgenesis: Implications for Screening and for Molecular PathophysiologyJournal of Clinical Endocrinology & Metabolism, 2002
- Discordant KCNQ1OT1 imprinting in sets of monozygotic twins discordant for Beckwith-Wiedemann syndromeHuman Molecular Genetics, 2002
- Gonadal Determination and Adrenal Development Are Regulated by the Orphan Nuclear Receptor Steroidogenic Factor-1, in a Dose-Dependent MannerJournal of Clinical Endocrinology & Metabolism, 2002
- Nongenetic Male PseudohermaphroditismThe New England Journal of Medicine, 2002
- Steroidogenic Factor 1: an Essential Mediator of Endocrine DevelopmentProceedings of the 1972 Laurentian Hormone Conference, 2002
- A Naturally Occurring Steroidogenic Factor-1 Mutation Exhibits Differential Binding and Activation of Target GenesOnline Journal of Public Health Informatics, 2000