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Human minimal androgen insensitivity with normal dihydrotestosterone-binding capacity in cultured genital skin fibroblasts: evidence for an androgen-selective qualitative abnormality of the receptor.
Am J Hum Genet. 1984 Sep; 36(5):965-78.AJ

Abstract

We have studied a kindred in which two parts of siblings, maternal first cousins, have a form of "minimal" androgen insensitivity that permits morphogenesis of unambiguous male external genitalia, but interferes with normal virilization at puberty. All four had gynecomastia that required reductive surgery. Apart from this common phenotype, they varied considerably in the temporal and regional aspects of their subvirilization and appreciably in their androgenic responsiveness to pharmacological doses of testosterone. The cultured genital skin fibroblasts from one set of siblings have an androgen-receptor activity with the following properties: (1) a normal maximum-binding capacity (Bmax) with 5 alpha-dihydrotestosterone (DHT), or the synthetic androgen, methyltrienolone (MT; R1881) as ligand; (2) a higher than normal apparent equilibrium dissociation constant (Kd) for DHT (0.77 nM) but not for MT; and (3) an elevated dissociation rate (k) of DHT-receptor (0.013 min-1, 37 degrees C), but not MT-receptor, complexes within intact cells. In addition, prolonged incubation with MT, but not DHT, augments the specific androgen-binding activity of the mutant cells as much as that of the controls. Normal cells yield lower values of apparent Kd for DHT (0.1-0.3 nM) after 2- than after 0.5-hr incubation (0.3-1.8 nM), and 1-hr values are intermediate. This occurs despite concurrent catabolic consumption of DHT from the medium and is considered to reflect transformation of initial, low-affinity DHT-receptor complexes to subsequent, higher-affinity states by a process that depends on time and initial ligand concentration. The mutant complexes described here can readily attain the highest state of affinity with MT, but have an impeded, variably expressed ability to do so with DHT. These findings suggest that a structural mutation at the X-linked locus that encodes the androgen-receptor protein is responsible for its androgen-selective dysfunction. Synthetic, nonhepatotoxic androgens, with corrective effects in vitro comparable to those of MT, may be therapeutically useful for these subjects.

Authors

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Pub Type(s)

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

Language

eng

PubMed ID

6333813

Citation

Pinsky, L, et al. "Human Minimal Androgen Insensitivity With Normal Dihydrotestosterone-binding Capacity in Cultured Genital Skin Fibroblasts: Evidence for an Androgen-selective Qualitative Abnormality of the Receptor." American Journal of Human Genetics, vol. 36, no. 5, 1984, pp. 965-78.
Pinsky L, Kaufman M, Killinger DW, et al. Human minimal androgen insensitivity with normal dihydrotestosterone-binding capacity in cultured genital skin fibroblasts: evidence for an androgen-selective qualitative abnormality of the receptor. Am J Hum Genet. 1984;36(5):965-78.
Pinsky, L., Kaufman, M., Killinger, D. W., Burko, B., Shatz, D., & Volpé, R. (1984). Human minimal androgen insensitivity with normal dihydrotestosterone-binding capacity in cultured genital skin fibroblasts: evidence for an androgen-selective qualitative abnormality of the receptor. American Journal of Human Genetics, 36(5), 965-78.
Pinsky L, et al. Human Minimal Androgen Insensitivity With Normal Dihydrotestosterone-binding Capacity in Cultured Genital Skin Fibroblasts: Evidence for an Androgen-selective Qualitative Abnormality of the Receptor. Am J Hum Genet. 1984;36(5):965-78. PubMed PMID: 6333813.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Human minimal androgen insensitivity with normal dihydrotestosterone-binding capacity in cultured genital skin fibroblasts: evidence for an androgen-selective qualitative abnormality of the receptor. AU - Pinsky,L, AU - Kaufman,M, AU - Killinger,D W, AU - Burko,B, AU - Shatz,D, AU - Volpé,R, PY - 1984/9/1/pubmed PY - 1984/9/1/medline PY - 1984/9/1/entrez SP - 965 EP - 78 JF - American journal of human genetics JO - Am. J. Hum. Genet. VL - 36 IS - 5 N2 - We have studied a kindred in which two parts of siblings, maternal first cousins, have a form of "minimal" androgen insensitivity that permits morphogenesis of unambiguous male external genitalia, but interferes with normal virilization at puberty. All four had gynecomastia that required reductive surgery. Apart from this common phenotype, they varied considerably in the temporal and regional aspects of their subvirilization and appreciably in their androgenic responsiveness to pharmacological doses of testosterone. The cultured genital skin fibroblasts from one set of siblings have an androgen-receptor activity with the following properties: (1) a normal maximum-binding capacity (Bmax) with 5 alpha-dihydrotestosterone (DHT), or the synthetic androgen, methyltrienolone (MT; R1881) as ligand; (2) a higher than normal apparent equilibrium dissociation constant (Kd) for DHT (0.77 nM) but not for MT; and (3) an elevated dissociation rate (k) of DHT-receptor (0.013 min-1, 37 degrees C), but not MT-receptor, complexes within intact cells. In addition, prolonged incubation with MT, but not DHT, augments the specific androgen-binding activity of the mutant cells as much as that of the controls. Normal cells yield lower values of apparent Kd for DHT (0.1-0.3 nM) after 2- than after 0.5-hr incubation (0.3-1.8 nM), and 1-hr values are intermediate. This occurs despite concurrent catabolic consumption of DHT from the medium and is considered to reflect transformation of initial, low-affinity DHT-receptor complexes to subsequent, higher-affinity states by a process that depends on time and initial ligand concentration. The mutant complexes described here can readily attain the highest state of affinity with MT, but have an impeded, variably expressed ability to do so with DHT. These findings suggest that a structural mutation at the X-linked locus that encodes the androgen-receptor protein is responsible for its androgen-selective dysfunction. Synthetic, nonhepatotoxic androgens, with corrective effects in vitro comparable to those of MT, may be therapeutically useful for these subjects. SN - 0002-9297 UR - https://www.unboundmedicine.com/medline/citation/6333813/Human_minimal_androgen_insensitivity_with_normal_dihydrotestosterone_binding_capacity_in_cultured_genital_skin_fibroblasts:_evidence_for_an_androgen_selective_qualitative_abnormality_of_the_receptor_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/6333813/ DB - PRIME DP - Unbound Medicine ER -