SF1 in the development of the adrenal gland and gonads.
SF1 (steroidogenic factor-1; NR5A1) is an orphan nuclear receptor that is expressed in the adrenal gland, gonads, spleen, ventromedial hypothalamus and pituitary gonadotroph cells. Combined approaches of targeted mutagenesis in mice and examination of the effects of naturally occurring mutations in humans have clarified the role of SF1 in steroidogenesis and development. Targeted disruption of SF1 (FTZF1) in mice prevents gonadal and adrenal development and causes male-to-female sex reversal. A heterozygous loss-of-function human SF1 mutation (G35E) was described in a patient with adrenal failure and complete 46,XY sex reversal, indicating that haploinsufficiency of this transcription factor is sufficient to cause a severe clinical phenotype. In an infant with a similar clinical phenotype, a homozygous SF1 mutation (R92Q) was identified. In functional assays, this mutant SF1 protein exhibited partial loss of DNA binding and transcriptional activity when compared with the more severe G35E P-box mutant. These patients reveal the exquisite sensitivity of SF1-dependent developmental pathways to gene dosage and function in humans.
Ozisik
Gokhan
G
Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University, The Feinberg School of Medicine, Chicago, Ill, USA.
Achermann
John C
JC
Meeks
Joshua J
JJ
Jameson
J Larry
JL
D000311:Adrenal Glands / Q000196:embryology*; D000818:Animals; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012734:Disorders of Sex Development; D005314:Embryonic and Fetal Development; D051717:Fushi Tarazu Transcription Factors; D018628:Gene Dosage; D006066:Gonads / Q000196:embryology*; D018398:Homeodomain Proteins; D006720:Homozygote; D006801:Humans; D051379:Mice; D009154:Mutation / Q000502:physiology; D010641:Phenotype; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D054339:Steroidogenic Factor 1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016335:Zinc Fingers
D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; D051717:Fushi Tarazu Transcription Factors; D018398:Homeodomain Proteins; C539965:NR0B1 protein, human; C515057:NR5A1 protein, human; C539966:Nr0b1 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; C515058:steroidogenic factor 1, mouse