Phenotypic spectrum of mutations in DAX-1 and SF-1

Mol Cell Endocrinol. 2001 Dec 20;185(1-2):17-25. doi: 10.1016/s0303-7207(01)00619-0.


SF-1 (steroidogenic factor-1) (NR5A1) and DAX-1 (dosage-sensitive sex-reversal, adrenal hypoplasia congenital, X chromosome) (NR0B1) are orphan nuclear receptors that are expressed in the adrenal gland, gonads, ventromedial hypothalamus (VMH), and pituitary gonadotrope cells. The function of these genes has been clarified by examining the consequences of naturally occurring mutations in humans, as well as targeted disruption of the genes in mice. Mutations in DAX1 cause adrenal hypoplasia congenita (AHC), an X-linked disorder characterized by adrenal insufficiency and failure to undergo puberty because of hypogonadotropic hypogonadism. Most DAX1 mutations introduce frameshifts and/or cause premature termination of the protein. Relatively few missense mutations have been described and all are located within the carboxy-terminal half of the protein. Transfection assays demonstrate that AHC-associated DAX1 mutations abrogate its ability to act as a transcriptional repressor of SF-1. Most boys affected with AHC present with adrenal insufficiency in early infancy, although a significant fraction present in later childhood or even as young adults. The degree of gonadotropin deficiency is also variable. With the exception of one mild missense DAX1 mutation, genotype-phenotype correlations have been elusive, suggesting an important role for modifier genes. Targeted mutagenesis of Dax1 (Ahch) in mice reveals an additional role in testis development and spermatogenesis. Similar abnormalities appear to be present in humans. Targeted mutagenesis of Sf1 (FtzF1) prevents gonadal and adrenal development, and causes male-to-female sex-reversal. A human XY individual with a heterozygous SF1 mutation presented with adrenal insufficiency and complete sex-reversal; this DNA-binding domain mutation prevents SF-1 stimulation of its target genes. In addition to their clinical relevance, studies of SF1 and DAX1 are proving useful for unraveling the genetic pathways that govern adrenal and gonadal development.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Adrenal Glands / growth & development
  • Animals
  • DAX-1 Orphan Nuclear Receptor
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology
  • Female
  • Fushi Tarazu Transcription Factors
  • Genetic Variation
  • Homeodomain Proteins
  • Humans
  • Male
  • Mutagenesis, Site-Directed
  • Mutation*
  • Phenotype
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid / genetics*
  • Receptors, Retinoic Acid / metabolism
  • Receptors, Retinoic Acid / physiology
  • Repressor Proteins*
  • Steroidogenic Factor 1
  • Testis / growth & development
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcription Factors / physiology


  • DAX-1 Orphan Nuclear Receptor
  • DNA-Binding Proteins
  • Fushi Tarazu Transcription Factors
  • Homeodomain Proteins
  • NR0B1 protein, human
  • NR5A1 protein, human
  • Nr0b1 protein, mouse
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid
  • Repressor Proteins
  • Steroidogenic Factor 1
  • Transcription Factors