PMID- 10022458
OWN - NLM
STAT- MEDLINE
DCOM- 19990225
LR  - 20141120
IS  - 0021-972X (Print)
IS  - 0021-972X (Linking)
VI  - 84
IP  - 2
DP  - 1999 Feb
TI  - Discordant measures of androgen-binding kinetics in two mutant androgen receptors
      causing mild or partial androgen insensitivity, respectively.
PG  - 805-10
AB  - We have characterized two different mutations of the human androgen receptor
      (hAR) found in two unrelated subjects with androgen insensitivity syndrome (AIS):
      in one, the external genitalia were ambiguous (partial, PAIS); in the other, they
      were male, but small (mild, MAIS). Single base substitutions have been found in
      both individuals: E772A in the PAIS subject, and R871G in the MAIS patient. In
      COS-1 cells transfected with the E772A and R871G hARs, the apparent equilibrium
      dissociation constants (Kd) for mibolerone (MB) and methyltrienolone are normal. 
      Nonetheless, the mutant hAR from the PAIS subject (E772A) has elevated
      nonequilibrium dissociation rate constants (k(diss)) for both androgens. In
      contrast, the MAIS subject's hAR (R871G) has k(diss) values that are apparently
      normal for MB and methyltrienolone; in addition, the R871G hAR's ability to bind 
      MB resists thermal stress better than the hAR from the PAIS subject. The E772A
      and R871G hARs, therefore, confer the same pattern of discordant androgen-binding
      parameters in transfected COS-1 cells as observed previously in the subjects'
      genital skin fibroblasts. This proves their pathogenicity and correlates with the
      relative severity of the clinical phenotype. In COS-1 cells transfected with an
      androgen-responsive reporter gene, trans-activation was 50% of normal in cells
      containing either mutant hAR. However, mutant hAR-MB binding is unstable during
      prolonged incubation with MB, whereas normal hAR-MB binding increases. Thus,
      normal equilibrium dissociation constants alone, as determined by Scatchard
      analysis, may not be indicative of normal hAR function. An increased k(diss)
      despite a normal Kd for a given androgen suggests that it not only has increased 
      egress from a mutant ligand-binding pocket, but also increased access to it. This
      hypothesis has certain implications in terms of the three-dimensional model of
      the ligand-binding domain of the nuclear receptor superfamily.
FAU - Shkolny, D L
AU  - Shkolny DL
AD  - Lady Davis Institute for Medical Research, Sir M. B. Davis-Jewish General
      Hospital, Montreal, Quebec, Canada.
FAU - Beitel, L K
AU  - Beitel LK
FAU - Ginsberg, J
AU  - Ginsberg J
FAU - Pekeles, G
AU  - Pekeles G
FAU - Arbour, L
AU  - Arbour L
FAU - Pinsky, L
AU  - Pinsky L
FAU - Trifiro, M A
AU  - Trifiro MA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Clin Endocrinol Metab
JT  - The Journal of clinical endocrinology and metabolism
JID - 0375362
RN  - 0 (Androgens)
RN  - 0 (Receptors, Androgen)
RN  - 0 (Testosterone Congeners)
RN  - 2C323EGI97 (Metribolone)
RN  - 6PG9VR430D (Nandrolone)
RN  - 9OGY4BOR8D (mibolerone)
SB  - IM
MH  - Amino Acid Sequence
MH  - Androgen-Insensitivity Syndrome/*genetics
MH  - Androgens/*metabolism
MH  - Animals
MH  - COS Cells
MH  - Drug Stability
MH  - Female
MH  - Hot Temperature
MH  - Humans
MH  - Male
MH  - Metribolone/metabolism
MH  - Molecular Sequence Data
MH  - Mutagenesis, Site-Directed
MH  - Nandrolone/analogs & derivatives/metabolism
MH  - *Point Mutation
MH  - Receptors, Androgen/chemistry/*genetics
MH  - Testosterone Congeners/metabolism
MH  - Transcriptional Activation
MH  - Transfection
EDAT- 1999/02/18 00:00
MHDA- 1999/02/18 00:01
CRDT- 1999/02/18 00:00
PHST- 1999/02/18 00:00 [pubmed]
PHST- 1999/02/18 00:01 [medline]
PHST- 1999/02/18 00:00 [entrez]
AID - 10.1210/jcem.84.2.5453 [doi]
PST - ppublish
SO  - J Clin Endocrinol Metab. 1999 Feb;84(2):805-10. doi: 10.1210/jcem.84.2.5453.