Tags

Type your tag names separated by a space and hit enter

Familial external genital ambiguity due to a transformation defect of androgen-receptor complexes that is expressed with 5 alpha-dihydrotestosterone and the synthetic androgen methyltrienolone.
Am J Med Genet. 1984 Jul; 18(3):493-507.AJ

Abstract

We have studied various properties of the binding of 5 alpha-dihydrotestosterone (DHT) or the synthetic, nonmetabolizable androgen methyltrienolone (R1881; 17 beta-hydroxy-17 alpha-methylestra-4,9,11-trien-3-one) to the androgen receptor of genital skin fibroblasts (GSF) from controls and a subject with familial, receptor-positive, partial androgen insensitivity. The mutant cells form R1881-receptor complexes that dissociate 7 times more rapidly than normal at 30 degrees C, and they do not increase their specific R1881-receptor activity in response to a 72-hr period of incubation with R1881, whereas the cells from normal individuals do so two- to three-fold. As previously reported [Pinsky et al, 1981; Kaufman et al, 1981], the mutant cells have similar abnormalities with DHT as with R1881. When the patient's cells are incubated for 120 min with varying concentrations (0.05-3 nM) of R1881 or DHT, Scatchard analysis shows that their androgen-receptor activity has an apparent equilibrium dissociation constant (Kd) for each ligand that is six-fold greater than that of normal cells (approximately 0.2 nM). Normal GSF have higher, more variable values of Kd (0.3-1.8 nM) for either ligand after 30 compared to 120 min of incubation, and the 60-min values are intermediate. This explains why we previously reported that the patient's cells had a 30-min Kd for DHT in the normal range [Pinsky et al, 1981]. Sucrose gradient centrifugation of mutant GSF cytosol incubated with DHT in the presence of 10 mM sodium molybdate yields a normal 6.5-8S peak of DHT-receptor complexes. From these data we conclude that normal GSF form initial, low-affinity androgen-receptor complexes that are transformed into one (or more) higher-affinity (? activated) states by a process that depends on time and initial concentration of androgen; the subject's GSF can form low-affinity androgen-receptor complexes but cannot generate the normal high-affinity state of the complexes, and this lack precludes augmentation of their androgen-receptor activity in response to prolonged incubation with either androgen; and failure of molybdate to stabilize the androgen-receptor activity in GSF cytosol is not a more sensitive indicator of structurally altered androgen-receptor proteins than are other qualities described heretofore.

Authors

No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Case Reports
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

6332533

Citation

Kaufman, M, et al. "Familial External Genital Ambiguity Due to a Transformation Defect of Androgen-receptor Complexes That Is Expressed With 5 Alpha-dihydrotestosterone and the Synthetic Androgen Methyltrienolone." American Journal of Medical Genetics, vol. 18, no. 3, 1984, pp. 493-507.
Kaufman M, Pinsky L, Bowin A, et al. Familial external genital ambiguity due to a transformation defect of androgen-receptor complexes that is expressed with 5 alpha-dihydrotestosterone and the synthetic androgen methyltrienolone. Am J Med Genet. 1984;18(3):493-507.
Kaufman, M., Pinsky, L., Bowin, A., & Au, M. W. (1984). Familial external genital ambiguity due to a transformation defect of androgen-receptor complexes that is expressed with 5 alpha-dihydrotestosterone and the synthetic androgen methyltrienolone. American Journal of Medical Genetics, 18(3), 493-507.
Kaufman M, et al. Familial External Genital Ambiguity Due to a Transformation Defect of Androgen-receptor Complexes That Is Expressed With 5 Alpha-dihydrotestosterone and the Synthetic Androgen Methyltrienolone. Am J Med Genet. 1984;18(3):493-507. PubMed PMID: 6332533.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Familial external genital ambiguity due to a transformation defect of androgen-receptor complexes that is expressed with 5 alpha-dihydrotestosterone and the synthetic androgen methyltrienolone. AU - Kaufman,M, AU - Pinsky,L, AU - Bowin,A, AU - Au,M W, PY - 1984/7/1/pubmed PY - 1984/7/1/medline PY - 1984/7/1/entrez SP - 493 EP - 507 JF - American journal of medical genetics JO - Am. J. Med. Genet. VL - 18 IS - 3 N2 - We have studied various properties of the binding of 5 alpha-dihydrotestosterone (DHT) or the synthetic, nonmetabolizable androgen methyltrienolone (R1881; 17 beta-hydroxy-17 alpha-methylestra-4,9,11-trien-3-one) to the androgen receptor of genital skin fibroblasts (GSF) from controls and a subject with familial, receptor-positive, partial androgen insensitivity. The mutant cells form R1881-receptor complexes that dissociate 7 times more rapidly than normal at 30 degrees C, and they do not increase their specific R1881-receptor activity in response to a 72-hr period of incubation with R1881, whereas the cells from normal individuals do so two- to three-fold. As previously reported [Pinsky et al, 1981; Kaufman et al, 1981], the mutant cells have similar abnormalities with DHT as with R1881. When the patient's cells are incubated for 120 min with varying concentrations (0.05-3 nM) of R1881 or DHT, Scatchard analysis shows that their androgen-receptor activity has an apparent equilibrium dissociation constant (Kd) for each ligand that is six-fold greater than that of normal cells (approximately 0.2 nM). Normal GSF have higher, more variable values of Kd (0.3-1.8 nM) for either ligand after 30 compared to 120 min of incubation, and the 60-min values are intermediate. This explains why we previously reported that the patient's cells had a 30-min Kd for DHT in the normal range [Pinsky et al, 1981]. Sucrose gradient centrifugation of mutant GSF cytosol incubated with DHT in the presence of 10 mM sodium molybdate yields a normal 6.5-8S peak of DHT-receptor complexes. From these data we conclude that normal GSF form initial, low-affinity androgen-receptor complexes that are transformed into one (or more) higher-affinity (? activated) states by a process that depends on time and initial concentration of androgen; the subject's GSF can form low-affinity androgen-receptor complexes but cannot generate the normal high-affinity state of the complexes, and this lack precludes augmentation of their androgen-receptor activity in response to prolonged incubation with either androgen; and failure of molybdate to stabilize the androgen-receptor activity in GSF cytosol is not a more sensitive indicator of structurally altered androgen-receptor proteins than are other qualities described heretofore. SN - 0148-7299 UR - https://www.unboundmedicine.com/medline/citation/6332533/Familial_external_genital_ambiguity_due_to_a_transformation_defect_of_androgen_receptor_complexes_that_is_expressed_with_5_alpha_dihydrotestosterone_and_the_synthetic_androgen_methyltrienolone_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0148-7299&date=1984&volume=18&issue=3&spage=493 DB - PRIME DP - Unbound Medicine ER -