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Original Studies |
Department of Obstetrics and Gynecology, National University of Singapore, Republic of Singapore 119074; and the Institute for Reproduction and Development, Monash University (A.T., D.d.K.), and Prince Henry’s Institute of Medical Research (R.M.), Melbourne, Victoria 3168, Australia
Address all correspondence and requests for reprints to: Assoc. Prof. E. L. Yong, Department of Obstetrics and Gynecology, National University Hospital, Lower Kent Ridge Road, Republic of Singapore 119074. E-mail: obgyel{at}nus.edu.sg
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Glu) in
residue 798 of the AR gene. This germline mutation was pathogenic
because it was not observed in fertile controls, was associated with
features of minimal androgen insensitivity in our patient, has been
related to more severe grades of androgen insensitivity, and caused a
subtle, but significant, decrease in receptor
trans-activation function in vitro that
is consistent with the phenotype. Despite being located in the middle
of the ligand-binding domain of the receptor, the Q798E mutation did
not cause any ligand binding defect, indicating that this highly
conserved residue has a trans-activation function but
does not directly form part of the ligand binding pocket of the
receptor. The trans-activation defect of the mutant
receptor can be rectified in vitro with the androgenic
drug, fluoxymesterone, but not with mesterolone or nortestosterone.
Further studies are required to determine the therapeutic relevance of
this finding. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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): the trans-activation
domain (TAD), the DNA-binding domain, and the ligand-binding domain
(LBD). Androgens, when bound to the LBD, activate the receptor, causing
nuclear translocation of the ligand-receptor complex and a series of
molecular events leading to the trans-activation of
androgen-regulated genes (13).
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Patients with male infertility were recruited from infertility clinics associated with the National University of Singapore and Monash University (Melbourne, Australia). A complete medical history was obtained, and a physical examination was undertaken. Peripheral blood was obtained for karyotyping, hormonal analyses, and DNA isolation. Control samples were obtained from 110 fertile males with no history of subfertility and whose wives attended a contraceptive clinic. The project was approved by the medical ethics committees of the National University Hospital, Singapore, and Monash Medical Center.
Single strand conformation polymorphism (SSCP) analyses and sequencing
Exon 6 of the AR gene from 234 subfertile males and 110 controls was examined by PCR-SSCP with specific primers and silver staining as previously described (22). Alleles with differential migration were purified and sequenced to ascertain the exact mutation. The nonpolymorphic regions of exon 1 were examined with specific primers (12). The length of the polymorphic CAG tract was measured (18). Mutant alleles were rechecked with a second blood sample to prevent errors in sample labeling. The presence of other pathogenic AR mutations was excluded by sequencing both the sense and antisense strands of other exons using primers (12) located in flanking introns.
Construction of Q798E expression plasmid
We used the primer extension method to introduce the mutation
into the AR expression vector, pSVhAR.BHEXE (15). Briefly, to create
the CG (CAAGAA) base change in codon 798 of the AR complementary
DNA (cDNA), we designed the following two internal primers (with
mutated nucleotide underlined): sense primer F, 5'-G TTT GGA
TGG CTC GAA ATC ACC-3'; and antisense primer R, 3'-C AAA
CCT ACC GAG CTT TAG TGG-5'.
We used the forward primer B (5'-GTG TCA CAC ATT GAA GGC TAT G-3') in exon 4, and the reverse primer A (5'-CTG GGT GTG GAA ATA GAT GGG CTT GA-3') in exon 8 as outside primers. Initially, two primary PCRs were performed separately using pSVhAR.BHEXE as the template: primers B and R for fragment 1, and primers F and A for fragment 2, using cloned Pfu polymerase. These overlapping, primary amplification products were then denatured and allowed to anneal together to produce a heteroduplex product with overhanging ends. The recessed ends of the heteroduplexes were extended by cloned Pfu DNA polymerase to produce a fragment that is the sum of the two overlapping products. A subsequent reamplification was performed for 30 cycles using primers A and B to generate the mutant cDNA fragment. The secondary PCR product was purified and double digested with XhoI and EcoRI to generate sticky ends for ligation into a pSVhAR.BHEXE fragment with the equivalent fragment excised. The mutant AR construct was sequenced to ensure the correctness of site-directed mutagenesis.
Transient transfection of mammalian cell lines
Mutant and wild-type (WT) plasmid constructs were transfected
into COS-7, CV-1, or HeLa cells, using the lipofection technique (18).
The use of COS cells ensures a high level of receptor expression for
the study AR ligand binding. CV-1 cells were used in
trans-activation studies because the reporter gene,
pMAMneo-LUC (Clontech, Palo Alto, CA) containing the
luciferase gene coupled to the mouse mammary tumor virus long terminal
repeat (MMTV-LTR) gave the greatest response to androgen in this cell
line. The MMTV-LTR has several androgen response elements (ARE), which
makes it a strong promoter when activated by ligand-bound AR. In some
experiments, HeLa cells were cotransfected with a luciferase reporter
gene containing a synthetic multimeric ARE ([ARE]2-Tata-Luc) (23).
Transfected cells were exposed to androgens for 48 h before the
harvesting and measurement of luciferase activity. The androgens used
included dihydrotestosterone (DHT); the non-metabolizable androgen,
miborelone (MB); androgen analogs used in the treatment of defective
spermatogenesis, fluoxymesterone
(9
-fluoro-11ß-hydroxy-17-methyltestosterone)
and mesterolone (1-methylandrostan-17ß-ol-3-one); and the
androgenic anabolic steroid, 19-nortestosterone (nandrolone,
4-estren-17ß-ol-3-one; all from Sigma Chemical Co., St.
Louis, MO). In some experiments, replicate wells were exposed to a
saturating dose (3 nmol/L) of [3H]MB, and specific
radiolabeled androgen bound was measured (15) to estimate the WT and
mutant AR protein contents at each treatment level.
Androgen-binding properties of receptors
The ligand-binding properties of mutant and control AR were studied in transfected COS-7 cells (15). In brief, confluent monolayer cultures were transiently transfected with WT or mutant AR expression vector and then exposed to increasing doses of tritiated androgen. After the incubation, the isotope solution was discarded, and [3H]androgen specifically bound to cells was measured to obtain the Scatchard plot. Chase studies were performed by measuring the dissociation rates of bound [3H]androgen in cells exposed to a 200-fold excess of unlabeled ligand. Androgen binding at higher temperatures was measured by comparing the amounts of [3H]androgen specifically bound at 42 C relative to that bound at 30 C, the scrotal temperature. Thermolability was present if the differences in relative binding between WT and mutant receptors was more than 40%. All data points are the means of quadruplicate samples.
Western analysis
Immunoblot analysis was used to study the AR protein levels using the rabbit antibody, NH27, which recognizes the first 27 N-terminal amino acids of the human AR. The AR protein-antibody complexes were subsequently visualized by enhanced chemiluminescence (18). The AR protein band, of about 110 kDa, was confirmed by its absence in extracts of untransfected CV-1 cells and its presence in the LNCaP prostate cancer cells.
Data analysis
Statistical analyses were performed using a SPSS software package (SPSS, Inc. Chicago, IL). Each data point is the mean ± SE of at least triplicate experiments. ANOVAs were used to examine overall changes in trans-activation activity between WT and mutant AR, and the Mann-Whitney test was then applied to assess the significance of differences of each dose at each treatment. Tukey’s test was used for multiple comparisons of the effects of androgenic drugs on the function of the mutant AR. P < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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G transition in nucleotide 2754 altering the sense of codon 798
from glutamine (Q) to glutamic acid (E; Fig. 1
, A and B). The mutation
created a new TaqI site in exon 6 (Fig. 1C). In contrast, no
mutations were detected in exon 6 of 110 fertile controls. There were
no other sequence abnormalities in exons 2–8 or in the nonpolymorphic
regions of exon 1 of the patient. He had 20 CAG repeats in the
polymorphic region of exon 1 (normal range, 14–31 CAGs). The mutant AR
was from a Caucasian patient who presented to the Monash In Vitro
Fertilization Center with primary infertility of 12-month duration.
Repeated semen analyses showed azoospermia. He was moderately obese,
with a body mass index of 29.7 kg/m2 (normal, <25). He had
sparse facial and axillary hair, suggesting a minimal degree of
androgen insensitivity. Other secondary sexual characteristics were
normal. In particular, his penis, scrotum, and pubic hair distribution
appeared normal, and no varicocele was detected. The testis measured 25
mL on both sides. He had no gynecomastia. His serum testosterone was
16.9 (normal, 10–33 nmol/L), FSH was 27.7 (normal, 1–9 IU/L), and LH
was 6.3 (normal, 2–12 IU/L). A testicular biopsy showed seminiferous
tubules, with marked peritubular fibrosis, that were lined by Sertoli
cells only, consistent with the Sertoli cell only syndrome. The Q798E
mutation was present in the germ line of the family, and the mother was
the carrier of the mutant allele (Fig. 1C).
As the mutation was in the LBD, we expressed and examined the
ligand-binding properties of the mutant AR. The mutant and WT AR were
exposed to increasing concentrations of radiolabeled androgen to obtain
the Scatchard plot (Fig. 2, left panels). When the cells
were exposed to MB, the equilibrium dissociation constants
(Kd) for WT and mutant AR were similar (0.52 and 0.50
nmol/L, respectively), and the corresponding Kd values for
DHT were 1.13 and 1.24 nmol/L, indicating that the Q798E mutation did
not affect the affinity of DHT or MB for the mutant receptor. To detect
subtle defects of ligand binding, the dissociation kinetics were
measured, where labeled ligand bound to AR was chased with an excess of
unlabeled ligand (Fig. 2, right
panels). The dissociation rates of DHT from WT and mutant
receptors were similar, with k values of 4.6 and 4.7 (10-3
min-1), respectively; the corresponding k values for MB
were 3.6 and 3.0 (10-3 min-1), indicating
that the mutation did not affect the dissociation kinetics of the
receptor. The proportions of MB bound at 42 C were 81% and 89% of the
values at 30 C for WT and mutant receptors, respectively, indicating
the absence of thermolability. Similarly, there was no thermolability
in DHT binding; at 42 C, WT and mutant receptors had 69% and 68% of
the binding observed at 30 C. Thus, this mutation, although residing in
the LBD, did not seem to affect any ligand-binding property of the
receptor.
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). At high doses of
MB (10 nmol/L), the trans-activation defect was less
evident, with the mutant having 87% of the WT trans
activity. The effects of different doses of AR plasmid were examined
(Fig. 3B), and for all doses of AR cDNA, the
trans-activation capacity of Q798E was less than that of WT
AR. WT AR induced a 17.2- to 18-fold increase in luciferase reporter
gene activity compared to the 14- to 16-fold rise observed with the
Q798E, indicating that the functional defect was not due to differences
in the amount of AR cDNA transfected. Trans-activation
experiments were repeated in a different cell line (HeLa) using a new
reporter gene containing a multimeric ARE ([ARE]2-Tata-Luc). These
experiments confirm that the mutant receptor had only 62–67% of the
trans-activation activity of the WT AR for doses of MB from
0.01–1 nmol/L (Fig. 3C), showing that the trans-activation
defect was intrinsic to the mutant receptor and was not dependent on
the ARE or cell line used. Mutant and WT AR protein contents were
quantified by measuring specific androgen binding in replicate wells at
each treatment dose (Fig. 3C, bottom panel). Specific
androgen binding measures AR protein content, as the mutant AR had no
abnormalities in ligand binding. The amounts of mutant and WT AR
protein were 145 ± 2.9 (mean ± SE) and 130
± 5.3 fmol AR/µg total protein, respectively (Fig. 3C, bottom
panel), and together with the immunoblot analyses in Fig. 3, A and
B, these results indicate that differences in AR protein content were
not the cause of the defective trans-activation. A
dose-response experiment was also performed with the physiological
androgen, DHT (Fig. 4, left
panel). The mutant AR had, again, only 65–78% (P
< 0.05, by Mann-Whitney test) of the trans-activation
capacity of the WT AR. These studies show that this amino acid
substitution resulted in a subtle, but consistent,
trans-activation defect, indicating the pathogenicity of the
mutation.
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, right panel). These
ligands were selected because they have been used in the empirical
treatment of male infertility (2). Dexamethasone, a nonandrogenic
steroid, did not increase trans-activation activity in
either WT or mutant AR, indicating that the mutation did not alter the
specificity of ligand binding. The mutant AR had only 59–67% of the
trans-activation activity of the WT when exposed to high
doses (100 nmol/L) of DHT, nortestosterone, mesterolone, and
fluoxymesterolone. The fold increase in trans-activation
activity observed with nortestosterone and mesterolone was similar to
that with DHT. On the other hand, fluoxymesterone, at both 10 and 100
nmol/L, induced a significantly higher (P < 0.001, by
Tukey test) mutant AR trans-activation activity than
equivalent doses of DHT, nortestosterone, or mesterolone (Fig. 4, right panel, faint line). Furthermore, fluoxymesterolone
restored mutant AR function to that observed with WT AR exposed to DHT.
A dose-response study with fluoxymesterone indicated that the increase
in luciferase activity was evident at a dose of 0.1 nmol/L, the
half-maximal dose was 0.15 nmol/L, and a maximal effect was achieved at
10 nmol/L (Fig. 5).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Glu mutation in residue 798, exon 6, of the AR
gene was identified in an azoospermic subject. Various lines of
evidence indicate that the mutant AR was causally related to defective
spermatogenesis and infertility. The mutation was found in our subject
with impaired sperm production, but not in 110 fertile controls. The
patient manifested sparse axillary and pubic hair development,
suggesting a minimal degree of androgen insensitivity. This mutation
had been observed in the genomic DNA of a 71-yr-old patient with
prostate carcinoma, who is married but has no children (24). The
association of Q798E AR with Reifenstein syndrome and ambiguous
genitalia (13, 16, 25) suggests that the mutation can result in
different grades of AR impairment, with varying phenotypes in different
individuals. Consistent with minimal disruption of receptor function
in vivo, the mutant receptor was partially active in
vitro, having consistently lower androgen-inducible
trans-activation activity than the WT receptor. Strikingly, the Q798E mutation, although residing in the LBD, did not affect any ligand-binding property of the AR. Of more than 200 LBD mutations recorded in the AR mutations database (26), almost all exhibited some form of ligand binding abnormality. A preliminary in vitro investigation in a subject with clitoromegaly and labial fusion had indicated that the trans-activation defect of this mutant AR was associated with normal affinity to MB (25). In this study, the ligand-binding properties of Q798E were examined in detail. The mutant AR displayed normal affinity (Kd) to the natural androgen, DHT, and the synthetic androgen, MB. Subtle abnormalities in dissociation kinetics or thermolability, reported in other cases of partial and minimal AIS (15, 27), were not detected. However, the trans-activation response of Q798E was consistently and significantly lower than that of WT AR for all androgens examined in two different cells lines (CV1 and HeLa) using reporter constructs containing either a natural (MMTV-LTR) or a multimeric ([ARE]2-Tata-Luc) ARE. Defective trans-activation was not due to differences in AR protein levels because WT and mutant AR protein content, quantified by [3H]androgen binding and immunoblot analyses, were similar. Moreover, the defect was still observed when transfection was performed with different doses of AR cDNA vector. These experiments indicate that the mutation reduced the intrinsic trans-activation capacity of the receptor, and that residue 798 of the AR does not contribute to the ligand binding pocket of the LBD but, instead, directly or via coactivators (23), affects the trans-activation function.
Although the correlation between receptor dysfunction in
vitro and sexual development is not absolute, AR mutations
associated with the female phenotype and complete AIS cause total
disruption of AR activity in reporter gene assays (13, 14), whereas AR
mutations in ambiguous genitalia and partial AIS reduce AR activity to
a lesser (
90–30% lower) degree (15, 25, 26). As spermatogenesis
requires high levels of androgens, the 35–22% lower
trans-activation activity of Q798E is consistent with
azoospermia and the absence of overt sexual ambiguity in our patient.
The ability of Q798E AR to cause varying degrees of androgen
insensitivity ranging from the partial (ambiguous genitalia) to minimal
(spermatogeneic defect) syndromes, indicate that the eventual phenotype
is influenced by the overall genetic background of the subject.
The glutamine residue in position 798 is highly conserved among members
of the steroid receptor family, being present in homologous positions
of the retinoic acid-X (RXR), glucocorticoid,
progesterone, and mineralocorticoid receptors (28). The
LBDs of RXR (29), retinoic acid (30), and estrogen (31) receptors are
similar in their architecture; the structural components comprise 11
-helixes and 2 ß-strands connected by linker regions. By comparing
the homologous regions of the AR and RXR-, it was observed that the
mutations associated with partial and minimal forms of androgen
insensitivity tend to cluster in the predicted linker regions between
the structural helixes of the AR (15). Strikingly, these predicted
linker regions also contain over 70% of the mutations associated with
the androgen-dependent tumor, prostate cancer. Residue 798 of the AR,
the site of the present mutation, is located in the predicted linker
region between helix 7 and helix 8. The clustering of these mutations
in the predicted linker regions suggests that these areas could have
important, but subtle, roles in defining hypo- or hyperfunction of the
AR.
Sperm production is exquisitely dependent on high androgen levels. Testicular testosterone concentrations are approximately 100-fold higher than those in serum, and studies in hypogonadal rats have shown that the administration of exogenous testosterone would, at low doses, result in disordered spermatogenesis; as further increments in testosterone are given, normal spermatogenesis is restored (32, 33). These studies have established that although spermatogenesis can proceed in the presence of intratesticular concentrations of testosterone approximately 10–15% of normal, these doses nevertheless cause prostatic and seminal vesicle hypertrophy, indicating that they are in excess with respect to levels in other androgen-sensitive tissues (34, 35). Although derived from a rodent model, these data suggest that spermatogenesis requires high doses of testosterone to achieve successful completion in comparison to other androgen-dependent tissues. It is interesting to note that the testicular volume in this man was normal despite azoospermia, high FSH levels, and a biopsy indicating Sertoli cell only syndrome. This finding may suggest that Sertoli cell fluid production, a major determinant in ensuring seminiferous tubule diameter, is maintained. We would speculate that the degree of androgen action achieved through the mutant receptor in our patient is sufficient to maintain the somatic cells of the testis but is inadequate for spermatogenesis. Further indications that the degree of androgen action achieved through the mutant receptor is adequate to maintain somatic structures emerges from the near-normal external genital development seen in this patient.
Androgen binding abnormalities have been reported in patients with male infertility (36). Testosterone (37) or other androgen analogues, such as fluoxymesterone and mesterolone, have been used empirically to treat cases of male infertility with inconsistent results. Fluoxymesterone has been used to improve sperm characteristics in the subfertile male (7), and the administration of 2–4 mg of the androgen daily for up to 12 months has been claimed to improve sperm motility and morphology (6). In a preliminary report, mesterolone successfully restored normal spermatogenesis and fertility in a subject with severely depressed sperm counts and AR mutation (38). On the other hand, a randomized double blind study on the effect of mesterolone in 157 couples with male infertility did not show any beneficial effect (9). Our study suggests that possible reasons for these conflicting reports include firstly, the relatively low incidence of AR mutations in males with idiopathic infertility resulting in a dilutional effect, and secondly, the differential response of the mutation to androgen analogues. The Q798E AR was tested with the androgen analogues, mesterolone and fluoxymesterone, and the anabolic androgen, nortestosterone. Nortestosterone and mesterolone did not improve the trans-activation function of the mutant AR. However, nanomolar doses of fluoxymesterone were able to restore mutant AR function to normal levels. Our in vitro studies provide a rational basis for selecting fluoxymesterone, if any androgen therapy is contemplated in this patient. However, such therapeutic use of androgen analogs is problematical, as androgens administered systemically could result in excess androgen action elsewhere with potentially harmful effects and through negative feedback inhibition of FSH and LH can reduce testicular androgen and sperm production further. Ideal androgen therapy in such patients awaits the development of a system that can deliver androgens directly and exclusively to the seminiferous tubule.
Although only one AR mutation was uncovered in exon 6, the presence of mutations in other exons (36, 38) and the association of polyglutamine polymorphisms of the AR with male infertility (18) indicate the increasing value of screening for mutations in the AR gene in patients with idiopathic male infertility. The Q798E mutation suggests a functional element(s) in the LBD that is not involved in ligand binding but that may have a role in the full trans-activation of genes necessary for sperm production.
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Acknowledgments |
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Footnotes |
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Received June 23, 1998.
Revised September 9, 1998.
Accepted September 16, 1998.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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. Nature. 375:377–382.[CrossRef][Medline]
ligand-binding domain bound to
all-trans retinoic acid. Nature. 378:681–689.[CrossRef][Medline]
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