Preserved male fertility despite decreased androgen sensitivity caused by a mutation in the ligand-binding domain of the androgen receptor gene
(2000) In Journal of Clinical Endocrinology and Metabolism 85(6). p.2253-2259- Abstract
Mutations in the androgen receptor gene are considered as incompatible with preservation of fertility and have been suggested as a cause of male infertility. Two adult brothers, referred because of gynecomastia and hormonal levels in serum indicating androgen insensitivity (high sex hormone-binding globulin, and LH levels, despite extremely high testosterone concentration), turned out to be relatives to a third young man, referred independently of the two others and exhibiting identical clinical and hormonal stigmata. In all three men, we found a C→A substitution at position 2470 (exon 7) in the androgen receptor gene, leading to a Gln824Lys mutation in the ligand-binding domain of the receptor. Exploring the family history revealed... (More)
Mutations in the androgen receptor gene are considered as incompatible with preservation of fertility and have been suggested as a cause of male infertility. Two adult brothers, referred because of gynecomastia and hormonal levels in serum indicating androgen insensitivity (high sex hormone-binding globulin, and LH levels, despite extremely high testosterone concentration), turned out to be relatives to a third young man, referred independently of the two others and exhibiting identical clinical and hormonal stigmata. In all three men, we found a C→A substitution at position 2470 (exon 7) in the androgen receptor gene, leading to a Gln824Lys mutation in the ligand-binding domain of the receptor. Exploring the family history revealed that their grandfathers, on their mothers' side, were brothers; and the Gln824Lys mutation was also found in the one of them who was still alive. Binding studies with the mutant receptor in transfected COS-7 cells, with mibolerone as ligand, exhibited equal Kd (0.7 vs. 1.0 nmol/ L), IC50 (0.8 vs. 1.1 nmol/L), and maximum binding (7.1 vs. 8.9 fmol/ 106 cells), as compared with the wild-type (WT) receptor. In a chloramphenicol acetyl transferase trans-activation assay, the activity of the mutant receptor was identical to that of the WT, when the synthetic androgen R1881 was used as a ligand; but with dihydrotestosterone, in concentrations up to 10 nmol/L, the activity of Gln824Lys mutated receptor was 10-62% of the WT variant. Thus, Gln824Lys mutation was found, both in vivo and in vitro, to cause slight impairment of receptor function but was compatible with preservation of male fertility. The patients inherited the mutation from their grandfathers through their mothers, and one of the young men possessing the mutation has fathered a daughter.
(Less)
- author
- Giwercman, Aleksander LU ; Kledal, Thomas ; Schwartz, Marianne ; Giwercman, Yvonne Lundberg LU ; Leffers, Henrik ; Zazzi, Henric ; Wedell, Anna and Skakkebæk, Niels E.
- publishing date
- 2000-12-01
- type
- Contribution to journal
- publication status
- published
- in
- Journal of Clinical Endocrinology and Metabolism
- volume
- 85
- issue
- 6
- pages
- 2253 - 2259
- publisher
- Oxford University Press
- external identifiers
-
- pmid:10852459
- scopus:0034458426
- ISSN
- 0021-972X
- DOI
- 10.1210/jcem.85.6.6626
- language
- English
- LU publication?
- no
- id
- 7272af43-4716-4669-93dc-be158b8095d9
- date added to LUP
- 2019-05-23 09:46:56
- date last changed
- 2024-07-24 18:48:19
@article{7272af43-4716-4669-93dc-be158b8095d9,
abstract = {{<p>Mutations in the androgen receptor gene are considered as incompatible with preservation of fertility and have been suggested as a cause of male infertility. Two adult brothers, referred because of gynecomastia and hormonal levels in serum indicating androgen insensitivity (high sex hormone-binding globulin, and LH levels, despite extremely high testosterone concentration), turned out to be relatives to a third young man, referred independently of the two others and exhibiting identical clinical and hormonal stigmata. In all three men, we found a C→A substitution at position 2470 (exon 7) in the androgen receptor gene, leading to a Gln824Lys mutation in the ligand-binding domain of the receptor. Exploring the family history revealed that their grandfathers, on their mothers' side, were brothers; and the Gln824Lys mutation was also found in the one of them who was still alive. Binding studies with the mutant receptor in transfected COS-7 cells, with mibolerone as ligand, exhibited equal K<sub>d</sub> (0.7 vs. 1.0 nmol/ L), IC<sub>50</sub> (0.8 vs. 1.1 nmol/L), and maximum binding (7.1 vs. 8.9 fmol/ 10<sup>6</sup> cells), as compared with the wild-type (WT) receptor. In a chloramphenicol acetyl transferase trans-activation assay, the activity of the mutant receptor was identical to that of the WT, when the synthetic androgen R1881 was used as a ligand; but with dihydrotestosterone, in concentrations up to 10 nmol/L, the activity of Gln824Lys mutated receptor was 10-62% of the WT variant. Thus, Gln824Lys mutation was found, both in vivo and in vitro, to cause slight impairment of receptor function but was compatible with preservation of male fertility. The patients inherited the mutation from their grandfathers through their mothers, and one of the young men possessing the mutation has fathered a daughter.</p>}},
author = {{Giwercman, Aleksander and Kledal, Thomas and Schwartz, Marianne and Giwercman, Yvonne Lundberg and Leffers, Henrik and Zazzi, Henric and Wedell, Anna and Skakkebæk, Niels E.}},
issn = {{0021-972X}},
language = {{eng}},
month = {{12}},
number = {{6}},
pages = {{2253--2259}},
publisher = {{Oxford University Press}},
series = {{Journal of Clinical Endocrinology and Metabolism}},
title = {{Preserved male fertility despite decreased androgen sensitivity caused by a mutation in the ligand-binding domain of the androgen receptor gene}},
url = {{http://dx.doi.org/10.1210/jcem.85.6.6626}},
doi = {{10.1210/jcem.85.6.6626}},
volume = {{85}},
year = {{2000}},
}