SUBSTITUTION OF VALINE-865 BY METHIONINE OR LEUCINE IN THE HUMAN ANDROGEN RECEPTOR CAUSES COMPLETE OR PARTIAL ANDROGEN INSENSITIVITY, RESPECTIVELY WITH DISTINCT ANDROGEN RECEPTOR PHENOTYPES

被引:63
作者
KAZEMIESFARJANI, P
BEITEL, LK
TRIFIRO, M
KAUFMAN, M
RENNIE, P
SHEPPARD, P
MATUSIK, R
PINSKY, L
机构
[1] UNIV MANITOBA, DEPT PHYSIOL, WINNIPEG R3T 2N2, MANITOBA, CANADA
[2] MCGILL UNIV, CTR HUMAN GENET, LADY DAVIS INST MED RES, DEPT BIOL, MONTREAL H3A 2T5, QUEBEC, CANADA
[3] MCGILL UNIV, CTR HUMAN GENET, DEPT MED, MONTREAL H3A 2T5, QUEBEC, CANADA
[4] MCGILL UNIV, CTR HUMAN GENET, DEPT PEDIAT, MONTREAL H3A 2T5, QUEBEC, CANADA
[5] CANC CONTROL AGCY, VANCOUVER, BC, CANADA
关键词
D O I
10.1210/me.7.1.37
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
We have identified two different single nucleotide missense substitutions at valine-865 in exon 7 of the human androgen receptor (AR) gene in two families with androgen resistance. Val --> methionine is associated with the complete syndrome; Val --> leucine is associated with the partial form. In genital skin fibroblasts, both alterations yield a normal maximum binding capacity, but an increased apparent equilibrium dissociation constant for all androgens tested. In genital skin fibroblasts, Val865-Met A-R complexes have increased rate constants of dissociation with 5alpha-dihydrotestosterone, and the nonmetabolized ligands methyltrienolone or mibolerone (MB); their Val865-Leu counterparts have increased rates with methyltrienolone and MB, but not with 5alpha-dihydrotestosterone. In transiently transfected COS-1 or PC-3 cells, Met865 AR is more severely impaired than Leu865 AR in transactivating two different androgen-responsive reporter constructs, thereby correlating with clinical phenotype. In COS-1 cells exposed to MB for 74 h, this relative impairment correlates with the relative instability of the MB-binding activity of each mutant AR, suggesting that their respective intrinsic transcriptional regulatory competence is normal. Notably, these mutant ARs lose significantly more MB-binding activity than immunoreactivity, suggesting that prolonged MB exposure induces them to adopt a nonbinding state. The position homologous to Val865 in the AR is occupied by Leu or Met in the three steroid receptors closely related to the AR. This indicates the structural subtlety that underlies the steroid-binding activity of different steroid receptors.
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页码:37 / 46
页数:10
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