Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function

J Clin Endocrinol Metab. 2007 Mar;92(3):991-9. doi: 10.1210/jc.2006-1672. Epub 2007 Jan 2.


Context: 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. Targeted deletion of Nr5a1 (Sf1) in the mouse results in adrenal and gonadal agenesis, XY sex-reversal, and persistent Müllerian structures in males. Consistent with the murine phenotype, human mutations in SF1 were described initially in two 46,XY individuals with female external genitalia, Müllerian structures (uterus), and primary adrenal failure.

Objective: Given recent case reports of haploinsufficiency of SF1 affecting testicular function in humans, we aimed to identify SF1 mutations in a cohort of individuals with a phenotypic spectrum of 46,XY gonadal dysgenesis/impaired androgenization (now termed 46,XY disorders of sex development) with normal adrenal function.

Methods and patients: The study included mutational analysis of NR5A1 in 30 individuals with 46,XY disorders of sex development, followed by functional studies of SF1 activity.

Results: Heterozygous missense mutations in NR5A1 were found in four individuals (four of 30, 13%) with this phenotype. These mutations (V15M, M78I, G91S, L437Q) were shown to impair transcriptional activation through abnormal DNA binding (V15M, M78I, G91S), altered subnuclear localization (V15M, M78I), or disruption of the putative ligand-binding pocket (L437Q). Two mutations appeared to be de novo or germline changes. The other two mutations appeared to be inherited in a sex-limited dominant manner because the mother is heterozygous for the change.

Conclusions: These studies demonstrate that SF1 mutations are more frequent than previously suspected causes of impaired fetal and postnatal testicular function in 46,XY individuals.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adrenal Glands / physiopathology*
  • Amino Acid Sequence
  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • DNA-Binding Proteins / metabolism
  • Female
  • Gonadal Dysgenesis, 46,XY / genetics*
  • Gonadal Dysgenesis, 46,XY / physiopathology
  • Heterozygote
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Homeodomain Proteins / physiology
  • Humans
  • Infant
  • Male
  • Molecular Sequence Data
  • Mutant Proteins / genetics
  • Mutation, Missense*
  • Receptors, Cytoplasmic and Nuclear / genetics*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Cytoplasmic and Nuclear / physiology
  • Sequence Homology, Amino Acid
  • Sexual Development / genetics*
  • Steroidogenic Factor 1
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcription Factors / physiology


  • DNA-Binding Proteins
  • Homeodomain Proteins
  • Mutant Proteins
  • NR5A1 protein, human
  • Receptors, Cytoplasmic and Nuclear
  • Steroidogenic Factor 1
  • Transcription Factors
  • steroidogenic factor 1, mouse