TY - JOUR
T1 - A novel mutation in the steroidogenic acute regulatory protein gene promoter leading to reduced promoter activity
AU - Casal, A.J.
AU - Sinclair, V.J.P.
AU - Capponi, A.M.
AU - Nicod, J.
AU - Huynh-Do, U.
AU - Ferrari, Paolo
PY - 2006
Y1 - 2006
N2 - 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 mu M, 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.
AB - 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 mu M, 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.
U2 - 10.1677/jme.1.02082
DO - 10.1677/jme.1.02082
M3 - Article
C2 - 16901925
VL - 37
SP - 71
EP - 80
JO - Journal of Molecular Endocrinology
JF - Journal of Molecular Endocrinology
SN - 0952-5041
ER -