title: A novel mutation in the steroidogenic acute regulatory protein gene promoter leading to reduced promoter activity.
abstract: We have identified a novel cytosine/thymidine polymorphism of the human steroidogenic acute regulatory (StAR) gene promoter located 3 bp downstream of the steroidogenic factor-1 (SF-1)-binding site and 9 bp upstream of the TATA box (ATTTAAG). Carriers of this mutation have a high prevalence of primary aldosteronism. In transfection experiments, basal StAR promoter activity was unaltered by the mutation in murine Y-1 cells and human H295R cells. In Y-1 cells, forskolin (25 microM, 6 h) significantly increased wild-type promoter activity to 230+/-33% (P<0.05, n=4). In contrast, forskolin increased mutated promoter activity only to 150+/-27%, with a significant 35% reduction compared to wild type (P<0.05, n=3). In H295R cells, angiotensin II (AngII; 10 nM) increased wild-type StAR promoter activity to 265+/-22% (P<0.01, n=3), while mutated StAR promoter activity in response to AngII only reached 180+/-29% of controls (P< 0.01, n=3). Gel mobility shift assays show the formation of two additional complexes with the mutated promoter: one with the transcription repressor DAX-1 and another with a yet unidentified factor, which strongly binds the SF-1 response element. Thus, this novel mutation in the human StAR promoter is critically involved in the regulation of StAR gene expression and is associated with reduced promoter activity, a finding relevant for adrenal steroid response to physiological stimulators.
authors.affiliation: Division of Endocrinology, Diabetology & Nutrition, University Hospital, Geneva 1211, Switzerland.
authors.forename: Andres J
authors.initials: AJ
authors.lastname: Casal
authors.forename: Victoria J P
authors.initials: VJ
authors.lastname: Sinclair
authors.forename: Alessandro M
authors.initials: AM
authors.lastname: Capponi
authors.forename: Jérôme
authors.initials: J
authors.lastname: Nicod
authors.forename: Uyen
authors.initials: U
authors.lastname: Huynh-Do
authors.forename: Paolo
authors.initials: P
authors.lastname: Ferrari
mesh_terms: D000818:Animals; D001483:Base Sequence; D051836:COUP Transcription Factors / Q000378:metabolism; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D003596:Cytosine / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D016415:Sequence Alignment; D016329:Sp1 Transcription Factor / Q000378:metabolism; D054339:Steroidogenic Factor 1; D013936:Thymidine / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D051836:COUP Transcription Factors; D018398:Homeodomain Proteins; C515057:NR5A1 protein, human; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D016329:Sp1 Transcription Factor; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; D000098682:Steroidogenic Acute Regulatory Protein; C515058:steroidogenic factor 1, mouse; D003596:Cytosine; D000242:Cyclic AMP; D013936:Thymidine