COMPLETE ANDROGEN INSENSITIVITY DUE TO MUTATIONS IN THE PROBABLE ALPHA-HELICAL SEGMENTS OF THE DNA-BINDING DOMAIN IN THE HUMAN ANDROGEN RECEPTOR

被引:43
作者
BEITEL, LK
PRIOR, L
VASILIOU, DM
GOTTLIEB, B
KAUFMAN, M
LUMBROSO, R
ALVARADO, C
MCGILLIVRAY, B
TRIFIRO, M
PINSKY, L
机构
[1] MCGILL UNIV, SIR MORTIMER B DAVIS JEWISH GEN HOSP, LADY DAVIS INST, MONTREAL H3A 1B1, PQ, CANADA
[2] MCGILL UNIV, DEPT BIOL, MONTREAL H3A 1B1, PQ, CANADA
[3] MCGILL UNIV, DEPT HUMAN GENET, MONTREAL H3A 1B1, PQ, CANADA
[4] MCGILL UNIV, DEPT MED, MONTREAL H3A 1B1, PQ, CANADA
[5] MCGILL UNIV, DEPT PEDIAT, MONTREAL H3A 1B1, PQ, CANADA
[6] UNIV BRITISH COLUMBIA, DEPT MED GENET, VANCOUVER V6H 3N1, BC, CANADA
基金
英国医学研究理事会;
关键词
D O I
10.1093/hmg/3.1.21
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
We describe different single-amino acid aberrations in the DNA-binding domain (DBD) of the human androgen receptor (hAR) in three families with complete androgen insensitivity. No additional alteration was found in the translated portion of each mutant gene. In one family, an in-frame 3 nt deletion removes codon 581 (or 582) and, thereby, one of two phenylalanines that invariably occupy adjacent positions in the N-terminal alpha-helical region of the DBD in the steroid/thyroid/vitamin D receptor superfamily. In the second, an in-frame 3 nt loss deletes Arg614, an invariant residue in the C-terminal alpha-helix of the DBD. In the third, a G-->A transition causes Arg614His. Following transient transfection of COS cells with each mutant AR plasmid, there is a normal concentration of specific androgen-binding activity that has a reduced ability to bind two types of androgen response element (ARE), and to transregulate an androgen-responsive human growth hormone reporter gene. In genital skin fibroblasts with Delta Phe581 or Arg614His, androgen-binding, AR protein and AR mRNA are markedly reduced; in gonadal fibroblasts with Delta Arg614, AR mRNA may be reduced. Our data substantiate the primary contributions of Phe581 and Arg614 to normal hAR-ARE binding, and expose important secondary effects of the mutations affecting each residue.
引用
收藏
页码:21 / 27
页数:7
相关论文
共 53 条
  • [1] THE HUMAN ANDROGEN RECEPTOR - DOMAIN-STRUCTURE, GENOMIC ORGANIZATION AND REGULATION OF EXPRESSION
    BRINKMANN, AO
    FABER, PW
    VANROOIJ, HCJ
    KUIPER, GGJM
    RIS, C
    KLAASSEN, P
    VANDERKORPUT, JAGM
    VOORHORST, MM
    VANLAAR, JH
    MULDER, E
    TRAPMAN, J
    [J]. JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, 1989, 34 (1-6) : 307 - 310
  • [2] PURIFICATION AND CHARACTERIZATION OF ANDROGEN RECEPTOR FROM STEER SEMINAL-VESICLE
    CHANG, CH
    ROWLEY, DR
    LOBL, TJ
    TINDALL, DJ
    [J]. BIOCHEMISTRY, 1982, 21 (17) : 4102 - 4109
  • [3] STRUCTURAL-ANALYSIS OF COMPLEMENTARY-DNA AND AMINO-ACID SEQUENCES OF HUMAN AND RAT ANDROGEN RECEPTORS
    CHANG, CS
    KOKONTIS, J
    LIAO, SS
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1988, 85 (19) : 7211 - 7215
  • [4] CHANG YT, 1991, 73RD ANN M END SOC W, P37
  • [5] CYTOCHEMICAL ANALYSIS OF ANDROGEN RECEPTOR REGULATION IN LNCAP CELLS AND GENITAL SKIN FIBROBLASTS
    CHOUDHRY, R
    PARKER, G
    HODGINS, MB
    [J]. ANNALS OF THE NEW YORK ACADEMY OF SCIENCES-SERIES, 1993, 684 : 211 - 213
  • [6] THE MOUSE GLUCOCORTICOID RECEPTOR - MAPPING OF FUNCTIONAL DOMAINS BY CLONING, SEQUENCING AND EXPRESSION OF WILD-TYPE AND MUTANT RECEPTOR PROTEINS
    DANIELSEN, M
    NORTHROP, JP
    RINGOLD, GM
    [J]. EMBO JOURNAL, 1986, 5 (10) : 2513 - 2522
  • [7] DIMERIZATION OF MAMMALIAN PROGESTERONE RECEPTORS OCCURS IN THE ABSENCE OF DNA AND IS RELATED TO THE RELEASE OF THE 90-KDA HEAT-SHOCK PROTEIN
    DEMARZO, AM
    BECK, CA
    ONATE, SA
    EDWARDS, DP
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1991, 88 (01) : 72 - 76
  • [8] SITE-DIRECTED MUTAGENESIS USING A DOUBLE-STRANDED DNA FRAGMENT AS A PCR PRIMER
    GIEBEL, LB
    SPRITZ, RA
    [J]. NUCLEIC ACIDS RESEARCH, 1990, 18 (16) : 4947 - 4947
  • [9] Gilliland G., 1990, PCR PROTOCOLS GUIDE, P60, DOI 10.1016/B978-0-12-372180-8.50012-3
  • [10] A C-ERB-A BINDING-SITE IN RAT GROWTH-HORMONE GENE MEDIATES TRANSACTIVATION BY THYROID-HORMONE
    GLASS, CK
    FRANCO, R
    WEINBERGER, C
    ALBERT, VR
    EVANS, RM
    ROSENFELD, MG
    [J]. NATURE, 1987, 329 (6141) : 738 - 741