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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2008-0737
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 10 3691-3696
Copyright © 2008 by The Endocrine Society

CLINICAL CASE SEMINAR

A Novel Mutation in the Human Androgen Receptor Suggests a Regulatory Role for the Hinge Region in Amino-Terminal and Carboxy-Terminal Interactions

A. Deeb, J. Jääskeläinen, M. Dattani, H. C. Whitaker, C. Costigan and I. A. Hughes

University Department of Paediatrics (A.D., J.J., I.A.H.), Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 2QQ, United Kingdom; Institute of Child Health and Great Ormond Street Hospital (M.D.), University College London, London WC1N 1EH, United Kingdom; Cancer Research United Kingdom Uro-Oncology Group (H.C.W.), Department of Oncology, University of Cambridge, Cambridge CB2 2XZ, United Kingdom; and Our Lady’s Hospital for Sick Children (C.C.), Crumlin, Dublin 12, Ireland

Address all correspondence and requests for reprints to: Professor I. A. Hughes, University Department of Pediatrics, Addenbrooke’s Hospital, Level 8, Box 116, Hills Road, Cambridge CB2 2QQ, United Kingdom. E-mail: iah1000{at}cam.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: The androgen insensitivity syndrome (AIS) is caused by molecular defects in the androgen receptor (AR). Clinically, the partial AIS has a variable phenotype. Many mechanisms explain the phenotype in the AIS. A crucial step in AR action is the interaction of the N and C termini.

Objective: The role of the hinge region of the AR is not as well understood as other parts of the receptor. We aim to study the role of this region in the N/C-termini interaction.

Patient and Method: We report a patient with severe undermasculinization and poor response to exogenous androgens. Androgen binding was performed, and the AR gene was sequenced. The mutation was recreated and transfected in COS-1 cells. Transactivation was studied. N/C-termini interaction was studied using a mammalian two-hybrid assay. A nuclear localization study was performed.

Results: Androgen binding was normal, and a novel mutation (Arg629Trp) in the AR hinge region was identified. Mutant AR transactivation was 40% higher compared with wild type (WT). A 3-fold increase in transcription occurred when both WT N and C-terminal domains were cotransfected; no response occurred when the mutated region of the AR was included (P < 0.001). Cells with mutant AR showed a comparable nuclear localization to the WT AR.

Conclusions: A mutation in the hinge region impaired N/C-domain interaction in the presence of normal AR binding and nuclear localization. It resulted in severe undermasculinization at birth and resistance to androgens. The findings confirm a unique regulatory role for the hinge region in AR function.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
The androgen insensitivity syndrome (AIS) is caused by mutations in the X-linked androgen receptor (AR) gene (1, 2). This results in abnormal development of internal and external male genitalia in 46, XY individuals. The complete AIS is characterized by external female genitalia, absence of müllerian structures, and a blind-ending vagina. Testes producing normal amounts of androgens aromatized to estrogens leads to breast development at puberty. The partial AIS (PAIS) manifests as male phenotype with hypospadias and micropenis, or as a female with clitoromegaly (3). Another variant is male with infertility, termed mild AIS (4).

The AR has three major domains: the N-terminal transactivation domain, a central DNA-binding domain (DBD), and a ligand binding domain (LBD) (5). Between the DBD and LBD lies the hinge region, defined by AR residues 628–669 (6) (Fig. 1Go).


Figure 1
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  		FIG. 1. A cartoon of the different functional domains of the AR and the corresponding coding exons. The location of FXXLF and WXXLF residues and the AF1and AF2 subdomains are shown.

 
Over 500 different AR mutations causing AIS are reported; most are missense mutations in the LBD (7) (http://www.mcgill.ca/androgendb). A number of mechanisms explain how the mutation affects AR function. One key step depends on N/C-terminal interaction.

The AR contains an activation function 2 (AF2) in the LBD and an activation function 1 (AF1) in the N-terminal region (Fig. 1Go). In the N terminus, there are two residues (FXXLF and WXXLF) that are important for LBD interaction and stabilizing the hormone-receptor complex (8, 9). The C-terminal sites linked to N/C interaction include amino acids in LBD helices 5, 9, 12, and those located between helices 3 and 4, or 7 and 8 (9, 10). Mutations here impair receptor function due to defective N/C interaction. Missense AR mutations in the hinge region are rarely reported in association with the AIS (11). Hiort et al. (11) provide information on function of the hinge region.

We report a male with the PAIS who required repeated surgery to correct severe hypospadias. Micropenis failed to respond to high-dose androgens despite normal androgen binding in genital skin fibroblasts. A novel mutation, Arg629Trp, in the hinge region disrupted N/C interaction. The AR hinge region may act constitutively to inhibit transcriptional activity, with transactivation and N/C-terminal interactions being independent functions. For this individual, a defect in AR action confined solely to disrupted N/C interaction is associated with severe androgen resistance.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patient

The subject presented with perineal hypospadias, micropenis, and a bifid scrotum containing gonads. He was the firstborn of nonconsanguineous parents and had two normal female siblings. No family history of genital ambiguity or infertility in maternal uncles was reported. Several surgical procedures were performed between the ages of 3 and 12 yr to correct the hypospadias. He developed bilateral gynecomastia (stage 4) at 15 yr of age; testes were 6 ml in volume bilaterally, pubic hair was stage 3, and there was no axillary hair. Penile length was 5 cm.

LHRH and human chorionic gonadotropin tests gave the following results, respectively: basal LH 15.7 IU/liter, peak LH 68.8; basal FSH 15.5 IU/liter, peak FSH 34.7; and basal testosterone 9.6 nmol/liter, peak testosterone 32.3. A urinary steroid profile excluded 5{alpha}-reductase deficiency. Karyotype was XY.

Testis volumes increased to 10 ml by 20 yr of age, but no further virilization. Final height was 172.5 cm (25th centile). He was azoospermic and had no erections but was able to ejaculate. There was no response to testosterone injections (250 mg every 3 wk) or topical dihydrotestosterone (DHT) gel. The fibroblast cell line was established from scrotal biopsy, and DNA was extracted. Ethics committee approval and informed consent from the patient were obtained.

Androgen binding assay

Androgen binding was analyzed as previously reported (12).

Molecular analysis

Genomic DNA was extracted from peripheral blood. AR exons 2–8 and the nonpolymorphic regions of exon 1 were amplified by PCR. Products were sequenced in both directions as previously reported (12, 13).

Plasmid constructs

The pSVAR expressing the full-length human AR cDNA was used (a gift from Dr. Albert Brinkmann, Department of Endocrinology and Reproduction, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands) (14). For the AR localization studies, pcDNA-FLAG-wtAR, a gift from Olli Jänne (Department of Physiology, Institute of Biomedicine, and Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland), was used (15). We used Kpn-I/{psi}-I digestion to introduce the AR mutation Arg629Trp into the pSVAR plasmid. Primers P1 and P4 are upstream and downstream of the AR cDNA Kpn-1/{psi}-1 sites, respectively (Table 1Go). Primers P2 and P3 were designed to contain the mutations to be incorporated into the pSVAR. PCR was performed in two stages. The fused PCR products were digested, and the digestion product containing the mutation was then subcloned back into the Kpn-1/{psi}-1 digested wild-type (WT) vector to generate a full-length AR cDNA containing the appropriate mutation. The sequence of the final mutant construct, pSVAR-Arg629Trp, was confirmed by sequencing. The reporter plasmid pGRE-LUC was a gift from Dr. Axel Alléra (Institut für Klinische Biochemie, Universität Bonn, Bonn, Germany). The pRL-TK (Promega Corp., Madison, WI) was used as an internal control of transfection efficiency.


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  		TABLE 1. Primers used in site-directed mutagenesis

 
For studies using the mammalian two-hybrid system, the pM-LBD and the pVP16-rAR-(5–538) were gifts from Dr. Jorma Palvimo (Biomedicum Helsinki, Institute of Biomedicine/Physiology, University of Helsinki, Helsinki, Finland) (16, 17). The point mutation Arg629Trp was incorporated into the LBD by the Quick Change Site-Directed Mutagenesis Kit (Stratagene, La Jolla, CA) and primers as described previously. The plasmid pCMX-UAS-TK-LUC (18) was used as a reporter and pRL-TK as an internal control. The mutated plasmid constructs were confirmed by direct sequencing.

Transfection

Cells were transfected using Transfast reagent (Promega).

Transactivation assay

COS-1 cells were then transfected with 250 ng WT or mutant pSVAR, 500 ng pGRE, 5 ng pRL-TK, and 2.265 µl Transfast reagent as directed by the manufacturer. A total of 0.1–100 nM {alpha}-DHT was added.

Cells were lysed and assayed using a dual luciferase assay system (Promega). The ratio of Firefly to Renilla luciferase units was measured using a Turner TD-20/20 luminometer (Turner Designs, Sunnyvale, CA).

The mammalian two-hybrid system to study N/C interaction

There were 2 x 105 COS-1 cells cultured with 10% dialyzed fetal bovine serum. After 24 h the cells were transfected with 250 ng WT or mutated pM-LBD, 250 ng pVP16-rAR-(5–538), 500 ng pCMX-UAS-TK-LUC, and 5 ng pRL-TK as an internal control for transfection efficiency. Transfast at 3 µl/µg transfected plasmid DNA was used. A final concentration of 10 nM 5{alpha} DHT was made. After 48 h incubation, the cells were lysed and assayed using a dual luciferase assay system.

Nuclear localization study

COS-1 cells were transfected with 50 ng of either pcDNA-FLAG-wtAR or psVAR-R629W per well using FuGENE6 (Roche Diagnostics Corp., Indianapolis, IN). The cells were incubated with 1, 10, or 100 nM DHT analog (R1881) (Sigma-Aldrich Corp., St. Louis, MO), or an equal volume of ethanol for a further 48 h. Cells were incubated for 1 h in 10% goat serum in PBS. Cells were probed for the AR (AR441, 1:200; Dako Corp., Carpinteria, CA), washed three times in PBS, and incubated for 30 min in 10% goat serum. Goat antimouse 488 antibody (Molecular Probes, Inc., Eugene OR) was used for detection. Cells were mounted using Vectashield containing 4',6-diamidino-2-phenylindole (DAPI) (Vector Laboratories, Burlingame, CA) to visualize the nuclei. An average of 16 images was captured using a Zeiss LSM 510 Meta confocal microscope (Carl Zeiss MicroImaging, Inc., Thornwood, NY).

Statistics

A nonparametric test (Mann-Whitney U test) was used to test the difference between the WT and mutant receptor. A P value of less than 0.05 was considered a significant difference.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
There was no evidence of a defect in androgen binding as based on normal Kd (Kd 0.9 x 10–10 M; normal range 0.8–1.7 x 10–10 M).

AR gene sequencing revealed a nucleotide change CGG->TGG at position 2247, resulting in the amino acid substitution Arg629Trp (R629W). This was not detected in 100 normal control X alleles of the same ethnic background of the patient. The number of CAG repeats was 29 (normal range 11–31).

Effects on transactivation

The transactivation efficiency of the mutant pSVAR-R629W and the WT pSVAR constructs were compared.

The response of both constructs was similar for DHT concentrations of 1 and 10 nM (Fig. 2Go). There was a trend toward exceeding the WTpSVAR response by 40% at the highest DHT concentration tested (100 nM). This difference was not statistically significant.


Figure 2
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  		FIG. 2. Comparison of the transactivation activity of WT and mutant receptor in response to 0–100 nM of DHT. Bars indicate the means, and error bars indicate SEMs.

 
Analysis of N/C-terminal interaction

Figure 3Go illustrates the effect of N and C-terminal interactions on luciferase reporter gene activity in the presence of DHT 10 nmol/liter. The response is expressed relative degree of transactivation of the pCMX-UAS-TK-LUC reporter. There was a 3-fold DHT induced activation with WT N and C-terminal domains compared with the terminal domain containing the mutant residue, R629W. The difference was statistically significant (P < 0.001).


Figure 3
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  		FIG. 3. Effect of WT and mutant LBD on receptor N/C interaction with DHT 10 nmol/liter. The y-axis indicates the relative activity of the reporter. The bars indicate the means, and the error bars indicate SEMs. LBD, pM-LBD; NTD, pVP16-rAR-(5–538); Reporter, pCMX-UAS-TK-LUC.

 
Nuclear localization study

Cells transfected with the WT AR showed complete receptor translocation to the nucleus at all concentrations of R1881 tested. Similarly, in cells transfected with the R629W, the AR appeared to translocate to the nucleus with only a slightly reduced efficiency compared with the WT AR (Fig. 4Go).


Figure 4
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  		FIG. 4. Androgen induced localization of AR in COS-7 cells. Confocal microscopy images showing representative graphs using 10 nM R1881. WT AR (wtAR) transfected COS-7 (top two sets) and cells transfected with R629W (bottom two sets) probed for AR (green) (1:200). Nuclei visualized with DAPI (blue). Scale bars, 10 µm. Comparison is shown between vehicle and R1881.

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The majority of AR mutations are located in the LBD; the few mutations found in the hinge region are generally somatic and associated with prostate cancer (7). We report a patient with a novel genomic mutation at codon 629 in the hinge region of the AR (Arg629Trp, R629W); high-dose androgen treatment failed to overcome the androgen resistance. Although androgen binding was normal, the AR gene was sequenced because the patient was so resistant to androgens. Normal androgen binding but failure to elicit transcriptional activity of the AR is well described in cases of AIS associated with mutations affecting the DBD. The majority cause complete AIS, but a number result in PAIS, particularly due to substitutions in exon 3 (19, 20, 21, 22).

We have identified a novel mutation in the hinge region, which does not affect ligand binding or nuclear localization but affects transcription by interrupting N/C-terminal interaction. The hinge region, defined in Fig. 1Go, is C terminal to the DBD and forms part of the bipartite nuclear localization signal (23). Nuclear localization requires residues 580–661, comprising the second zinc finger region of the DBD. Mutations affecting the nuclear localization signal result in the AR remaining predominantly cytoplasmic even in the presence of hormone (24). However, nuclear translocation was not significantly impaired by the R629W mutation, indicating this is not the cause of the PAIS phenotype.

Studies of the hinge region showed that deletion of residues 629–636 results in increased androgen responsiveness in vitro (25). Wang et al. (6) showed that deletion of residues 628–646 resulted in augmentation of the transactivation activity of the receptor. We postulate that this repressor activity of the hinge region was inhibited by the mutation detected in our patient, and the net result was augmentation of the transactivation activity. However, it has been shown that the requirement of N/C interaction for gene activation is promoter specific (26). We examined the transactivation with one promoter (reporter gene). However, there are several other androgen responsive genes of which many are dependent on this interaction.

The N-terminal domain residues FXXLF and WXXLF are necessary for ligand dissociation by interacting with the LBD to stabilize the hormone-receptor complex. Residue FXXLF mediates interaction between AF1 and AF2, a direct androgen-dependent process (8). Deleting the hinge region had no effect on AF1 (a region strongly active in the AR) and only an attenuating effect on AF2 (weakly active in the AR) (23).

Interaction between the N-terminal and C-terminal domains in an androgen-dependent manner is a characteristic feature of the AR (24). This intramolecular interaction specific to the AR is in addition to the generic nuclear receptor requirement for binding to coactivator proteins such as the P160 family (25). Disrupted N/C-terminal interaction due to mutations in the LBD is a recognized molecular abnormality in the AIS. We have previously reported that regions just before helix 3, between helices 5 and 6, and at helix 10 are also important for N/C-terminal interaction (27). To our knowledge the R629W genomic mutation identified in the hinge region in this patient with severe PAIS is the first report of this region of the AR being critical for N/C interaction.

Table 2Go summarizes other missense mutations reported in the hinge region in the AIS or prostate cancer. Mutation Ala645Asp was reported in a boy with the PAIS (11) but also in a normal boy with Wilms’ tumor (28). Studies suggest that the pathogenicity of this mutation may be modulated by the polymorphic repeats characteristic of the N terminus (29). Various mutations spanning helices 3–11 were detected in patients with the AIS. In comparison with our patient, some of these mutations (F725L, G743V, and F754L) exhibited normal androgen binding with reduced transactivation and attenuated N/C interactions. Other mutations (V715M, R726L, and M886V) had minor functional impairment (10).


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  		TABLE 2. Human AR hinge region (628–669) missense mutations and clinical phenotypes

 
Mutation Glu653Lys was reported in two families; the first had two girls with congenital adrenal hyperplasia in whom the degree of genital virilization was less than expected for their CYP21 genotype (30). The second example was a boy with the PAIS in whom functional studies of the mutant receptor showed reduced transcriptional activity. Mutation Ile664Asn was reported in the C terminus of the hinge region in a boy with the PAIS (31). The remaining AR hinge region mutations associated with the AIS are either large deletions or nonsense mutations.

Certain AIS mutations are known to be co-inherited with specific GGN lengths. For example, A645D mutation is linked to GGN10 and long CAG repeats (32). In our patient the CAG repeats were 29. It is interesting to study the impact of this length on the receptor function by cloning it into the expression vector together with the mutation. This study is planned in the future.

Missense mutations affecting the hinge region in the AIS are rare compared with those located in the DBD or LBD. They appear to cluster within the C-terminal part of the hinge region. However, we have described a novel Arg629Trp mutation that is located in the N-terminal part of the hinge region and demonstrates properties that suggest that the hinge region of the AR has a regulatory role in N/C interaction. This report is unique in documenting a novel AR mutation that has been fully characterized functionally and the results related to detailed outcome studies in a patient with severe PAIS raised male. There is evidence to support the role of the N-terminal part of the hinge region in N/C-terminal interaction. That this is important for AR-mediated male differentiation is illustrated by the nonresponsiveness in vivo to high doses of androgens given both systemically and topically. Furthermore, there was azoospermia that, unlike some milder forms of AIS, did not respond to androgen treatment The Consensus on intersex management highlighted the compelling need for outcome data on XY DSD, raised male (33). Armed with the kind of clinical and molecular information gained from studying novel AR gene mutations, such as R629W, clinicians can be better informed about prospects in adulthood for males with the PAIS.


   Acknowledgments
 
We thank Professor Albert Aynsley-Green, Professor David Powell, and Mr. Christopher Woodhouse for providing information on clinical management.


   Footnotes
 
Disclosure Statement: The authors have nothing to declare.

First Published Online August 12, 2008

Abbreviations: AF1, Activation function 1; AF2, activation function 2; AIS, androgen insensitivity syndrome; AR, androgen receptor; DAPI, 4',6-diamidino-2-phenylindole; DBD, DNA-binding domain; DHT, dihydrotestosterone; LBD, ligand binding domain; PAIS, partial androgen insensitivity syndrome; WT, wild type.

Received April 3, 2008.

Accepted July 31, 2008.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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