Human Molecular Genetics, 2000, Vol. 9, No. 5 829-834
© 2000 Oxford University Press
Longer polyglutamine tracts in the androgen receptor are associated with moderate to severe undermasculinized genitalia in XY males
1Department of Paediatrics, University of Cambridge, Box 116, Level 8, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK, 2Department of Paediatrics, Pamela Youde Nethersole Eastern Hospital, Lok Man Road, Chai Wan, Hong Kong, 3CRC Human Cancer Genetics Group, University of Cambridge, Strangeways Research Laboratory, Wort’s Causeway, Cambridge CB1 8RN, UK, 4MRC Biostatistics Unit, Institute of Public Health, University Forvie Site, Robinson Way, Cambridge CB2 2SR, UK, 55Incyte Europe, 214 Cambridge Science Park, Cambridge CB4 0WA, UK
Received 13 December 1999; Revised and Accepted 14 January 2000.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The androgen receptor (AR) is essential to the normal development of the male internal and external genitalia. Consequently, impairment of AR function can result in undermasculinized genitalia that vary from a completely female appearance to isolated hypospadias. Since in vitro studies demonstrate that AR function is reduced by expansion of the polyglutamine tract within the receptor [AR(Gln)n]; this study examined whether longer AR(Gln)n repeats are associated with moderate to severe undermasculinization. The average AR(Gln)n length of the undermasculinized group (n = 78, median 25, interquartile range 23–26) was significantly greater than that of the control population (n = 850, median 23, interquartile range 22–26, P = 0.002). The odds ratio of having
23 repeats (as opposed to 
22 repeats) in the undermasculinized group was 2.51 (95% confidence interval 1.41–4.48). The estimated increase in the OR for each additional repeat was 9.07%. Hormonal and AR binding data were used to select subgroups of patients that had a reduced likelihood of a sex steroid biosynthetic defect or an AR abnormality. A clear trend was demonstrated in which the mean AR(Gln)n length and the odds ratio increased with the rigour of the subgroup selection criteria. Undermasculinization of the male genitalia is a rare example of a non-neurodegenerative, congenital disorder that is associated with triplet repeat allele size. Furthermore, the association of both undermasculinized genitalia and isolated male factor infertility with AR(Gln)n length provides additional evidence that they may represent different degrees of severity of the same disease process. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The formation of the male reproductive system is a complex multi-step process that begins during embryogenesis and continues through puberty. In this lengthy process, it is the androgen receptor (AR) that mediates the actions of testosterone and 5
-dihydrotestosterone (DHT) to form the internal and external male genitalia, respectively (1). The AR is also essential to develop and maintain both secondary sexual characteristics and fertility. Mutations in the androgen receptor gene (AR) (located on chromosome Xq11) which severely impair the function of the receptor can result in a female phenotype known as the complete androgen insensitivity syndrome (CAIS). AR mutations that only partially impair AR function can result in a less severe phenotype known as the partial androgen insensitivity syndrome (PAIS). PAIS is an extremely heterogeneous disorder, varying from an almost completely female phenotype to normal male genitalia with infertility (2). Although PAIS is the most common diagnosis of undermasculinized genitalia in XY males (up to 37% in one estimate), most cases have no identifiable cause (3). The AR gene is also involved in the rare X-linked neurodegenerative disorder which presents in adulthood, known as spinal and bulbar muscular atrophy (SBMA) or Kennedy’s disease (4). In SBMA, there is a greater number of CAG repeats within the AR gene which results in longer polyglutamine tracts in the AR (40–62 repeats) than normal (11–31 repeats) (5,6). Longer polyglutamine tracts [AR(Gln)n] cause the AR to have reduced transcriptional activation, greater resistance to proteolysis and a tendency to aggregate (7–9). These AR aggregations can sequester proteins, including a co-factor for AR-induced transcription, known as the steroid receptor co-activator or SRC-1 (10). Decreased AR transcriptional activation and the sequestering of AR cofactors probably account for the features of mild androgen insensitivity, oligo- and azoospermia, testicular atrophy and gynaecomastia, which are associated with SBMA (11). Indeed, recent studies indicate that longer AR(Gln)n tracts within the normal range are associated with reduced spermatogenesis and infertility in otherwise normal males (12–14).
Despite the evidence that AR(Gln)n tracts are associated with androgen insensitivity in SBMA and infertility in normal males (which can be a manifestation of mild PAIS), it had not been determined whether an increased glutamine repeat length could also be associated with the more severe features of under- masculinized genitalia. Therefore, the aim of this study was to determine whether cases of ambiguous genitalia, with a similar phenotype to moderate to severe PAIS, have on average longer AR(Gln)n repeats than a control population.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The AR(Gln)n lengths were normally distributed in the control group, whereas there was a slight skew towards the larger repeats in the undermasculinized group (Fig. 1). In the undermasculinized group, none of the AR(Gln)n lengths (range 14–31) lay outside that of the control population (range 10–39). The median AR(Gln)n length in the control population [n = 850, median 23, interquartile range (IQR) 22–26] and the group with AR mutations (n = 46, median 22, IQR 20–24, mean 23.09) were not significantly different (P = 0.14), indicating that there was no bias for longer repeats within the population from which the database is derived. Furthermore, the average AR(Gln)n length of the undermasculinized group (n = 78, median 25, IQR 23–26, P = 0.002) was significantly greater than both the control population (n = 850, median 23, IQR 22–26) (Table 1) and the group with AR mutations (P = 0.002). The greater average number of AR(Gln)n repeats seen in the undermasculinized group was therefore not due to a poorly matched control population.
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The mean AR(Gln)n length was greater in the under- masculinized group (mean 24.46) than in the control group (mean 23.61) by 0.85 of a glutamine repeat. The mean AR(Gln)n length was further increased with the application of criteria to reduce the likelihood of a sex steroid biosynthetic defect within the undermasculinized group. Subgroup A with normal basal testosterone had a mean of 24.55, and those that also had a normal response to human chorionic gonadotrophin (hCG) stimulation (subgroup B) had a slightly higher mean AR(Gln)n length of 24.69. Subgroup C with evidence of normal DHT production (91% also had an appropriate rise in testosterone with hCG stimulation) showed a mean of 24.94, and a similar value of 24.93 was observed in the samples with normal AR binding data (subgroup D). Subgroup E containing those samples that met all the selection criteria had the greatest mean AR(Gln)n length (25.26). In all subgroups the median AR(Gln)n length is significantly greater than that of the control group (Table 1). Furthermore, a clear trend is apparent in which the mean AR(Gln)n length increases with the rigour of the subgroup selection criteria.
The odds ratios (ORs) between the control population and the undermasculinized group were compared for a range of repeat sizes (Table 2). The shortest repeat length to show a significant OR [OR = 2.51, 95% confidence interval (CI) 1.41–4.48] between the control and undermasculinized group was for 23 repeats compared with a repeat length 22. The longest repeat length for which there was a significant OR in the undermasculinized group (OR = 1.80, 95% CI 1.04–3.12) was for 27 repeats when compared with 26 repeats. For subgroups B, D and E, a significant OR was found for a polyglutamine tract of 28 repeats. The estimated percentage increase in the odds for undermasculinization for each additional repeat was estimated to be between 9.07 (undermasculinized group) and 16.85% (subgroup E) (Table 2).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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This study has demonstrated that cases of undermasculinized genitalia with physical features consistent with moderate to severe PAIS were associated with longer AR polyglutamine tracts. The AR binding data, basal testosterone levels, hCG stimulation tests, DHT measurements or urinary steroid profiles can be used to identify subgroups of patients with a mean AR(Gln)n length that is greater than the undermasculinized group as a whole. Conversely, from those samples not included in these subgroups [i.e. with shorter AR(Gln)n lengths] we can infer that, in the presence of a sex steroid biosynthetic defect or an abnormality of the AR, the length of the polyglutamine tracts is less important. This was demonstrated in the group of patients with known AR mutations where the mean AR(Gln)n length was the same as that of the control population. Furthermore, this indicates that the identification of additional patients with AR mutation that were not detected by AR binding would be expected to result in a further increase in mean AR(Gln)n length (in subgroups D and E). The presence of a relationship showing an increasing mean AR(Gln)n length and increasingly rigorous selection criteria for a subgroup, rather than an ad hoc finding, is further evidence that the effect of longer glutamine repeats is both real and important for a subset of patients. As there is a range of allele sizes encoding longer AR(Gln)n tracts, the association is unlikely to be due to linkage disequilibrium of certain triplet repeat lengths with another (causative) factor.
The repeat lengths in the undermasculinized group and subgroups fall within the normal range indicating that longer repeat lengths do not by themselves cause undermasculinization. This is further evidence that AR triplet repeat lengths within the normal range should not necessarily be regarded as benign or silent polymorphisms. The AR triplet repeat is therefore acting as a modifier locus. The other factors involved must be sufficiently subtle (i.e. do not by themselves always cause undermasculinization), that small increases in the number of glutamine repeats can influence either the manifestation of the disorder or its severity. Moderate to severe undermascu- linization of XY genitalia therefore appears to be a multi-factorial disorder involving longer polyglutamine repeat length, other genetic influences and possibly also environmental factors (15).
The magnitude of the difference in mean AR(Gln)n length in the undermasculinized groups compared with controls (a difference of between 0.85 of a glutamine for the under- masculinized group and 1.6 glutamines for subgroup E) might be expected from AR-induced transactivation data to result in only a small reduction in AR function and thus be of little clinical significance. However, the ORs show that, compared with controls, undermasculinized patients are two to three times as likely to have a longer AR(Gln)n repeat than a shorter length; and that for each additional repeat the estimated increase in risk is between 9.07 and 16.85%. The importance of small differences in AR(Gln)n repeat length has also been shown in other studies; Stanford et al. (16) calculated that the decrease in risk of prostate cancer for each additional AR(Gln)n repeat is as much as 3% (16). Similarly, for BRCA-1-associated breast cancer, the presence of a single additional repeat in the AR (from 28 to 29 repeats) can result in a diagnosis 4.5 years earlier (17). Therefore, crude transactivation studies appear to be a poor indicator of the important long-term biological effects of AR(Gln)n length.
Undermasculinization of male genitalia is a rare example of a non-neurodegenerative, congenital disorder that is associated with triplet repeat allele size. It has been proposed, due to the occurrence of abnormal AR binding studies and AR mutations in both undermasculinization and isolated male infertility, that these two conditions can represent different degrees of severity of the same disease process (18,19). The association of both disorders with longer AR(Gln)n repeats lends further credence to this proposal. Since there is good evidence linking decreased AR function with both longer polyglutamine repeat lengths and undermasculinization, the association of longer AR(Gln)n repeats has both a plausible biological mechanism and context. This information contributes towards the further understanding of the possible mechanisms involved in disorders resulting from reduced androgenization.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Seventy-eight patients (referred to as the undermasculinized group) were selected from the Cambridge intersex and ambiguous genitalia database using the minimal selection criteria of: a normal 46,XY karyotype, no relationship to other patients in the database, no other severe congenital abnormalities (or abnormalities known to be associated with genital malformations), no known cause for the clinical features, and a phenotype consistent with moderate to severe undermasculinization (grades 3–7) (2). Patients noted to have a uterus, which may indicate testicular dysgenesis, were not included in this study. Most patients had more than one feature of undermasculinization, with approximately half the cases having a partly fused or unfused scrotum, micropenis and a perineoscrotal urethral opening (n = 36) (Table 3). Local ethics committee approval was obtained for the use of patient samples as part of a sexual development disorders’ research program.
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The hormonal data were compared with age-appropriate reference ranges to identify subgroups less likely to have sex steroid biosynthetic defects (Table 3) (further details available on request) (20–23). Basal testosterone levels were measured in 69 of the 78 undermasculinized cases; 7 of these had low or equivocal levels and 62 were normal (referred to as subgroup A). Of those with normal basal testosterone levels, 55 cases also had an appropriate elevation in testosterone levels in response to hCG (subgroup B). A normal testosterone:DHT ratio or urinary steroid profile that made 5
-reductase deficiency an unlikely diagnosis was present in 47 of the 78 cases (subgroup C), most of whom (n = 43) also had an appropriate rise in testosterone with an hCG stimulation test. Since AR mutations most commonly occur in the androgen-binding domain, measurements of AR-binding capacity (Bmax) and AR-binding affinity (Kd) in genital skin fibroblasts are an effective method of screening for samples with mutations (24). AR binding studies had been performed in 57 of the 78 patients, of which 53 cases had normal values (subgroup D). In the four cases with abnormal AR binding (all had elevated Kd values) single-strand conformation polymorphism (SSCP) analysis of the coding region and exon–intron boundaries failed to detect mutations (unpublished data). Therefore, these samples were neither included in subgroup D (due to the possibility of an undetected mutation) nor classified as PAIS (known to have an AR mutation). Samples which met the selection criteria of all subgroups were analysed as subgroup E (n = 31).
The 425 control samples were randomly selected, anonymous females from East Anglia taking part in a population-based cohort study of diet and health (25,26). A further control group was included to ensure that any differences between the control and undermasculinized group was not due to a selection bias for sex, race, ethnicity or geography. An additional 46 cases (37 with CAIS and 9 with PAIS) were chosen from the Cambridge intersex and ambiguous genitalia database. All 46 patients had a characterized AR mutation and therefore inheritance of the AR(Gln)n repeat could not occur independently of the androgen insensitivity phenotype. Thus, the repeat length in these 46 patients with AR mutations should be representative of the population from which the database is collected.
The CAG repeat region (including the terminal CAA codon encoding glutamine) was PCR amplified and mixed with GS-500 ROX size standard and loading buffer, denatured and electrophoresed on an ABI 373 sequencer using Genescan software (reagents and equipment from PE Applied Biosystems, Warrington, UK) (26). Selected samples were electrophoresed on multiple gels to control for discrepancies between each run. The same PCR primers, sequencer and electrophoresis conditions were used for the undermasculinized and control samples. Eleven samples from the control set were examined in parallel with the patient samples to ensure consistency in allele scoring. Three samples of known sequence (12, 18 and 31 repeats) confirmed the precision of this method for determining the CAG repeat number and thus AR(Gln)n length.
To test for a difference in the median AR(Gln)n length between the control and undermasculinized groups, the Wilcoxon two-sample test was selected because the data were discrete and not considered normally distributed. Mean, median, IQR (25–75%), OR and 95% CI were calculated by standard methods. To determine the percentage increase in odds of disease for each additional repeat, logistic regression was used to model the disease status as a function of repeat length. The exponential of the fitted repeat length coefficient will give an estimate of the increase in odds of disease with each extra repeat. Statistical analysis was performed with S-plus 5.0 (MathSoft, Cambridge, MA).
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ACKNOWLEDGEMENTS |
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We thank Alan Schafer for critical comments on the manuscript. We are most grateful to Robert Luben and Suzy Oakes for access to the control (EPIC) samples. H.N.L. is supported by the Birth Defects Foundation and an Overseas Research Student award. S.M. and A.M.D. are supported by the Cancer Research Campaign.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +44 1223 336 885; Fax: +44 1223 336 996; Email: HL215@mole.bio.cam.ac.uk
§ Present address: Incyte Europe Ltd, 214 Science Park, Cambridge CB4 0WA, UK
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 A. Mifsud, A. T. Choon, D. Fang, and E.L. Yong Prostate-specific antigen, testosterone, sex-hormone binding globulin and androgen receptor CAG repeat polymorphisms in subfertile and normal men Mol. Hum. Reprod., November 1, 2001; 7(11): 1007 - 1013. [Abstract] [Full Text] [PDF]
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 I. A. Hughes Minireview: Sex Differentiation Endocrinology, August 1, 2001; 142(8): 3281 - 3287. [Abstract] [Full Text] [PDF]
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H. N. Lim, R. M. Nixon, H. Chen, I. A. Hughes, and J. R. Hawkins Evidence That Longer Androgen Receptor Polyglutamine Repeats Are a Causal Factor for Genital Abnormalities J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3207 - 3210. [Abstract] [Full Text] [PDF]
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K. Muroya, I. Sasagawa, Y. Suzuki, T. Nakada, T. Ishii, and T. Ogata Hypospadias and the androgen receptor gene: mutation screening and CAG repeat length analysis Mol. Hum. Reprod., May 1, 2001; 7(5): 409 - 413. [Abstract] [Full Text] [PDF]
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 I. A. Hughes A Novel Explanation for Resistance to Androgens N. Engl. J. Med., September 21, 2000; 343(12): 880 - 882. [Full Text]
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