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CAG repeat length of the androgen receptor gene in Japanese males with cryptorchidism

CAG repeat length of the androgen receptor gene in Japanese males with cryptorchidism Abstract We have analysed the CAG repeat length in exon 1 of the androgen receptor gene in 48 Japanese males with cryptorchidism and 100 fertile Japanese males. The CAG repeat length was 23.4 ± 0.48 (mean ± SE) (range 16–32, median 23) in cryptorchid patients and 23.5 ± 0.29 (range 15–32, median 23) in normal males. There was no significant difference between the two groups. The expansion of the CAG repeats in exon 1 of the androgen receptor gene is unlikely to constitute a major cause of cryptorchidism. androgen receptor, CAG repeat, cryptorchidism Introduction Normal male sexual differentiation, testicular descent, and spermatogenesis require androgens and a functional androgen receptor (AR). The AR gene has successfully been cloned and is localized at chromosome Xq12 (Lubahn et al., 1988). Its protein coding region comprises eight exons which code for various functional domains: exon 1 encodes the transactivation domain in the aminoterminal part of the protein, exons 2 and 3 encode the DNA binding domain, exon 4 encodes the hinge domain and exons 5–8 encode the ligand-binding domain (Lubahn et al., 1989). Mutations of the AR gene have been associated with various disorders including complete androgen insensitivity syndrome, various neuron diseases and prostate cancer (Lubahn et al., 1989; Hardy et al., 1996; Gottlieb et al., 1998). Most abnormalities in the AR gene have been identified in the DNA-binding and the ligand-binding domains (Quigley et al., 1995; Gottlieb et al., 1998) and only a few mutations have been reported in the transactivation domain (Gottlieb et al., 1998). The AR contains a polymorphic CAG repeat sequence for the polyglutamine tract in exon 1. Progressive expansion of the CAG repeat in human AR results in a linear decrease in transactivation function (Chamberlain et al., 1994). Consistent with this, expansion of the CAG repeat tract results in spinal bulbar muscular atrophy, a fatal neuromuscular disease characterized by low masculinization, oligozoospermia or azoospermia, testicular atrophy, and reduced fertility (La Spada et al., 1991), and mild but statistically significant expansion of the CAG repeat tract is often associated with azoospermia (Dowsing et al., 1999) and ambiguous genitalia in genetic males (Yong et al., 1998). The association between longer CAG repeats and male infertility has also been emphasized in other studies (Tut et al., 1997; Dowsing et al., 1999). In contrast, shorter CAG repeat tracts have been suggested to raise the susceptibility to prostate cancer, an androgen-dependent tumour (Giovannucci et al., 1997). It is well known that XY individuals with complete androgen insensitivity syndrome have undescended testes, suggesting that the presence of androgens and a functioning AR are necessary for the testes to descend (Wiener et al., 1997). However, there is no literature dealing with the association of expansion of the CAG repeat tracts with the occurrence of cryptorchidism. Therefore, we investigated CAG repeat length in patients and cryptorchidism. Materials and methods Patients This study included 48 Japanese patients with cryptorchidism and 100 control subjects. All the patients underwent surgical repair for cryptorchidism at the Yamagata University Hospital. They ranged in age from 1 to 32 years (mean 13). Seventeen patients had bilateral cryptorchidism, 29 had unilateral undescended testis and two had undescended monorchidism. The control subjects were males with proven fertility. They ranged in age from 23 to 42 years (mean 31). Chromosome analysis on peripheral lymphocytes showed a karyotype of 46,XY in all the patients and controls. Informed consent was obtained from all patients and their parents, and clinical information regarding them was concealed. CAG repeat analysis Genomic DNA was extracted from peripheral leukocytes of each subject by use of DNA isolation kit (Puregene; Gentra, Minneapolis, MN, USA), according to the manufacturer's protocol. Genomic DNA was amplified by polymerase chain reaction (PCR) with primers flanking the polymorphic CAG repeat region. Amplification was performed in a reaction volume of 20 μl containing 0.1 μg genomic DNA, 8 pmol fluorescently labelled forward primer (5′-TCCAGAATCTGTTCCAGAGCGTGC-3′), 8 pmol unlabelled reverse primer (5′-GCTGTGAAGGTTGCTGTTCCTCAT-3′), 0.1 mmol/l dNTPs, and 1 U Taq polymerase (Allen et al., 1992). PCR was performed for 30 cycles consisting of 45 s at 94°C, 45 s at 55°C, and 45 s at 72°C. The PCR products were mixed with internal control size markers and were electrophoresed on an autosequencer (ABI PRISM 310; Applied Biosystems, Perkin Elmer, Norwalk, CT, USA). The size of the PCR products was determined by GeneScan software. Furthermore, to confirm the correct CAG repeat length, the CAG repeat regions of 15 subjects with different CAG repeat numbers were subjected to direct sequencing on the autosequencer. The normality of the distribution of CAG repeat numbers was examined by the χ2-test. The statistical significance of the median was analysed by the Mann-Whitney's U-test, and that of the frequency of long CAG repeats (≥29) was examined by Fisher's exact probability test; P < 0.05 was considered as significant. Results Representative results are shown in Figure 1, and the data are summarized in Figure 2. The distribution of the CAG repeat lengths did not follow the normal distribution. The CAG repeat number was 23.4 ± 0.48 (mean ± SE) (range 16–32, median 23) for the patients with cryptorchidism and 23.5 ± 0.29 (range 15-32, median 23) for control subjects. The difference was not statistically significant between patients and controls. The CAG repeat number was 23.7 ± 0.64 (range 18–32, median 24) for the 31 patients with unilateral cryptorchidism, and 23.8 ± 0.69 (range 16–28, median 23) for the 17 patients with bilateral cryptorchidism; there was no significant difference between the two groups. Furthermore, two of the 48 patients and five of the 100 normal males had the long CAG repeat of ≥29. Thus, the frequency of long CAG repeat was comparable between the cryptorchid patients and the normal males. Discussion It is generally accepted that endocrine factors somehow play a major role in promoting the descent of the testes into the scrotum (Levy and Husmann, 1995). According to Hutson (1986), there are two stages of testicular descent. In the first stage, which may be controlled by Müllerian inhibiting substance (MIS), the testes migrate down towards the lower abdominal wall and reach the site of the future internal inguinal ring by the 7th month. In the second stage, the testes transit the abdominal wall via the inguinal canal and complete their passage into the bottom of the scrotum during the 28th week. Thus, the intra-abdominal portion of testicular descent is not androgen-mediated but the presence of functional androgens and AR is required for the testes to descend through the inguinal canal into the scrotum. In the present study, the size of the CAG repeat in exon 1 of the AR gene did not differ between patients with cryptorchidism and control males. This suggests that expansion of the CAG repeat tracts is unlikely to constitute a major cause of cryptorchidism. In addition, genetic analysis of isolated cryptorchid patients revealed no abnormalities of the coding sequences of exons 2 to 8 of the AR gene (Wiener et al., 1998). Although point mutations in the DNA and ligand domains of the AR are considered as a potential cause of cryptorchidism, these findings imply that the relevance of AR gene alterations to the development of isolated cryptorchidism is rare. It is well known that the size of the CAG repeat in exon 1 of the AR gene varies in a race-specific manner. A study from the USA has shown that the CAG repeat length in black men is significantly shorter than in non-Hispanic white men (Sartor et al., 1999). The prevalence of fewer than 22 CAG repeats was shown to be high in African Americans and low in Asians (Irvine et al., 1995). Furthermore, Chinese patients with defective spermatogenesis show expansion of the CAG repeats in the AR gene (Tut et al., 1997; Yong et al., 1998). Yoshida et al. (1999) also reported that Japanese males with idiopathic azoospermia have significantly longer CAG repeats than fertile Japanese males. In contrast, the size of the CAG repeat in the AR gene shows no significant relationship to impaired spermatogenesis in an infertile Caucasoid sample of German origin and a Swedish population of infertile patients (Giwercman et al., 1998; Dadze et al., 2000). The variability of the results by various investigators may be due to attributes of the different genetic origins of the populations studied (Yoshida et al., 1999; Dadze et al., 2000). In summary, the results imply that the CAG repeat tracts are unlikely to be expanded in patients with cryptorchidism. However, since the relevance of expanded CAG repeat tracts to the development of cryptorchidism remains possible in other patient populations, further studies are required to draw final conclusions on the relevance of CAG repeat length expansion to cryptorchidism. Figure 1. View largeDownload slide The CAG repeat length analysis by GeneScan (above) and direct sequencing (below) in two individuals with short (n = 18) and long (n = 31) CAG repeats. The short and long polymerase chain reaction (PCR) products are estimated as 263 bp and 299 bp in size, respectively, by the GeneScan analysis, and are shown to be 276 bp with 18 CAG repeats and 315 bp with 31 CAG repeats in size, respectively, by the direct sequencing. Because of the discrepancy inherent to GeneScan analysis, it is necessary to sequence each of PCR products with different sizes on GeneScan analysis. Figure 1. View largeDownload slide The CAG repeat length analysis by GeneScan (above) and direct sequencing (below) in two individuals with short (n = 18) and long (n = 31) CAG repeats. The short and long polymerase chain reaction (PCR) products are estimated as 263 bp and 299 bp in size, respectively, by the GeneScan analysis, and are shown to be 276 bp with 18 CAG repeats and 315 bp with 31 CAG repeats in size, respectively, by the direct sequencing. Because of the discrepancy inherent to GeneScan analysis, it is necessary to sequence each of PCR products with different sizes on GeneScan analysis. Figure 2. View largeDownload slide Distribution of the CAG repeat lengths in the controls (closed column) and cryptorchid patients (open column). Figure 2. View largeDownload slide Distribution of the CAG repeat lengths in the controls (closed column) and cryptorchid patients (open column). 3 To whom correspondence should be addressed at: Department of Urology, Yamagata University School of Medicine, 2-2-2 Iidanishi, Yamagata-shi, Yamagata 990-9585, Japan. E-mail: isasaga@med.id.yamagata-u.ac.jp References Allen, R.C., Zoghbi, H.Y., Moseley, A.B. et al. ( 1992) Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlated with X chromosome inactivation. Am. J. Hum. Genet. , 51, 1229–1239. Google Scholar Chamberlain, N.L., Driver, E.D. and Miesfeld, R.L. ( 1994) The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res. , 122, 3181-3186. Google Scholar Dadze, S., Wieland, C., Jakubiczka, S. et al. ( 2000) The size of the CAG repeat in exon 1 of the androgen receptor gene shows no significant relationship to impaired spematogenesis in an infertile Caucasoid sample of German origin. Mol. Hum. Reprod. , 6, 207–214. Google Scholar Dowsing, A.T., Yong, E.L., Clark, M. et al. ( 1999) Linkage between male infertility and trinucleotide repeat expansion in the androgen-receptor gene. Lancet , 354, 640–643. Google Scholar Giovannucci, E., Stampfer, M.J., Krithivas, K. et al. ( 1997) The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. Proc. Natl Acad. Sci. USA , 94, 3320–3323. Google Scholar Giwercman, Y.L., Xu, C., Arver, S. et al. ( 1998) No association between the androgen receptor gene CAG repeat and impaired sperm production in Swedish men. Clin. Genet. , 54, 435–436. Google Scholar Gottlieb, B., Lehvaslaiho, H., Beitel, L.K. et al. ( 1998) The androgen receptor gene mutations database. Nucleic Acids Res. , 26, 234–238. Google Scholar Hardy, D.O., Scher, H.I., Bogenreider, T. et al. ( 1996) Androgen receptor CAG repeat lengths in prostate cancer: correlation with age of onset. J. Clin. Endocrinol. Metab. , 81, 4400–4405. Google Scholar Hutson, J.M. ( 1986) Testicular feminization. A model for testicular descent in mice and men. J. Pediatr. Surg. , 21, 195–198. Google Scholar Irvine, R.A., Yu, M.C., Ross, R.K. and Coetzee, G.A. ( 1995) The CAG and GGC microsatellites of the androgen receptor gene are in linkage disequilibrium in men with prostate cancer. Cancer Res. , 55, 1937–1940. Google Scholar La Spada, A.R., Wilson, E.M., Lubahn, D.B. et al. ( 1991) Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature , 352, 77–79. Google Scholar Levy, J.B. and Husmann, D.A. ( 1995) The hormonal control of testicular descent. J. Androl. , 16, 459–463. Google Scholar Lubahn, D.B., Joseph, D.R., Sullivan, P.M. et al. ( 1988) Cloning of human androgen receptor complementary DNA and localisation of the X chromosome. Science , 240, 327–330. Google Scholar Lubahn, D.B., Brown, T.R., Simental, J.A. et al. ( 1989) Sequence of the intron/exon junctions of the coding region of the human androgen receptor gene and identification of a point mutation in a family with complete androgen insensitivity. Proc. Natl Acad. Sci. USA , 86, 9534–9538. Google Scholar Sartor, O., Zheng, Q. and Eastham, J.A. ( 1999) Androgen receptor gene CAG repeat length varies in a race-specific fashion in men without prostate cancer. Urology , 53, 378–380. Google Scholar Tut, T.G., Ghadessy, F., Trifiro, M.A. et al. ( 1997) Long glutamine tracts in the androgen receptor are associated with reduced transactivation, impaired sperm production and male infertility. J. Clin. Endocrinol. Metab. , 82, 3777–3782. Google Scholar Quigley, C.A., De Bellis, A., Marschke, K.B. et al. ( 1995) Androgen receptor defects: historical, clinical and molecular perspectives. Endocr. Rev. , 16, 271–321. Google Scholar Wiener, J.S., Teague, J.L., Roth, D.R. et al. ( 1997) Molecular biology and function of the androgen receptor in genital development. J. Urol. , 157, 1377–1386. Google Scholar Wiener, J.S., Marcelli, M., Gonzales, E.T. Jr et al. ( 1998) Androgen receptor gene alterations are not associated with isolated cryptorchidism. J. Urol. , 160, 863–865. Google Scholar Yong, E.L., Ghadessy, F., Wang, Q. et al. ( 1998) Androgen receptor transactivation domain and control of spermatogenesis. Rev. Reprod ., 3, 141–144. Google Scholar Yoshida, K., Yano, M., Chiba, K. et al. ( 1999) CAG repeat length in the androgen receptor gene is enhanced in patients with idiopathic azoospermia. Urology , 54, 1078–1081. Google Scholar © European Society of Human Reproduction and Embryology http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Molecular Human Reproduction Oxford University Press

CAG repeat length of the androgen receptor gene in Japanese males with cryptorchidism

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Publisher
Oxford University Press
Copyright
© European Society of Human Reproduction and Embryology
ISSN
1360-9947
eISSN
1460-2407
DOI
10.1093/molehr/6.11.973
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Abstract

Abstract We have analysed the CAG repeat length in exon 1 of the androgen receptor gene in 48 Japanese males with cryptorchidism and 100 fertile Japanese males. The CAG repeat length was 23.4 ± 0.48 (mean ± SE) (range 16–32, median 23) in cryptorchid patients and 23.5 ± 0.29 (range 15–32, median 23) in normal males. There was no significant difference between the two groups. The expansion of the CAG repeats in exon 1 of the androgen receptor gene is unlikely to constitute a major cause of cryptorchidism. androgen receptor, CAG repeat, cryptorchidism Introduction Normal male sexual differentiation, testicular descent, and spermatogenesis require androgens and a functional androgen receptor (AR). The AR gene has successfully been cloned and is localized at chromosome Xq12 (Lubahn et al., 1988). Its protein coding region comprises eight exons which code for various functional domains: exon 1 encodes the transactivation domain in the aminoterminal part of the protein, exons 2 and 3 encode the DNA binding domain, exon 4 encodes the hinge domain and exons 5–8 encode the ligand-binding domain (Lubahn et al., 1989). Mutations of the AR gene have been associated with various disorders including complete androgen insensitivity syndrome, various neuron diseases and prostate cancer (Lubahn et al., 1989; Hardy et al., 1996; Gottlieb et al., 1998). Most abnormalities in the AR gene have been identified in the DNA-binding and the ligand-binding domains (Quigley et al., 1995; Gottlieb et al., 1998) and only a few mutations have been reported in the transactivation domain (Gottlieb et al., 1998). The AR contains a polymorphic CAG repeat sequence for the polyglutamine tract in exon 1. Progressive expansion of the CAG repeat in human AR results in a linear decrease in transactivation function (Chamberlain et al., 1994). Consistent with this, expansion of the CAG repeat tract results in spinal bulbar muscular atrophy, a fatal neuromuscular disease characterized by low masculinization, oligozoospermia or azoospermia, testicular atrophy, and reduced fertility (La Spada et al., 1991), and mild but statistically significant expansion of the CAG repeat tract is often associated with azoospermia (Dowsing et al., 1999) and ambiguous genitalia in genetic males (Yong et al., 1998). The association between longer CAG repeats and male infertility has also been emphasized in other studies (Tut et al., 1997; Dowsing et al., 1999). In contrast, shorter CAG repeat tracts have been suggested to raise the susceptibility to prostate cancer, an androgen-dependent tumour (Giovannucci et al., 1997). It is well known that XY individuals with complete androgen insensitivity syndrome have undescended testes, suggesting that the presence of androgens and a functioning AR are necessary for the testes to descend (Wiener et al., 1997). However, there is no literature dealing with the association of expansion of the CAG repeat tracts with the occurrence of cryptorchidism. Therefore, we investigated CAG repeat length in patients and cryptorchidism. Materials and methods Patients This study included 48 Japanese patients with cryptorchidism and 100 control subjects. All the patients underwent surgical repair for cryptorchidism at the Yamagata University Hospital. They ranged in age from 1 to 32 years (mean 13). Seventeen patients had bilateral cryptorchidism, 29 had unilateral undescended testis and two had undescended monorchidism. The control subjects were males with proven fertility. They ranged in age from 23 to 42 years (mean 31). Chromosome analysis on peripheral lymphocytes showed a karyotype of 46,XY in all the patients and controls. Informed consent was obtained from all patients and their parents, and clinical information regarding them was concealed. CAG repeat analysis Genomic DNA was extracted from peripheral leukocytes of each subject by use of DNA isolation kit (Puregene; Gentra, Minneapolis, MN, USA), according to the manufacturer's protocol. Genomic DNA was amplified by polymerase chain reaction (PCR) with primers flanking the polymorphic CAG repeat region. Amplification was performed in a reaction volume of 20 μl containing 0.1 μg genomic DNA, 8 pmol fluorescently labelled forward primer (5′-TCCAGAATCTGTTCCAGAGCGTGC-3′), 8 pmol unlabelled reverse primer (5′-GCTGTGAAGGTTGCTGTTCCTCAT-3′), 0.1 mmol/l dNTPs, and 1 U Taq polymerase (Allen et al., 1992). PCR was performed for 30 cycles consisting of 45 s at 94°C, 45 s at 55°C, and 45 s at 72°C. The PCR products were mixed with internal control size markers and were electrophoresed on an autosequencer (ABI PRISM 310; Applied Biosystems, Perkin Elmer, Norwalk, CT, USA). The size of the PCR products was determined by GeneScan software. Furthermore, to confirm the correct CAG repeat length, the CAG repeat regions of 15 subjects with different CAG repeat numbers were subjected to direct sequencing on the autosequencer. The normality of the distribution of CAG repeat numbers was examined by the χ2-test. The statistical significance of the median was analysed by the Mann-Whitney's U-test, and that of the frequency of long CAG repeats (≥29) was examined by Fisher's exact probability test; P < 0.05 was considered as significant. Results Representative results are shown in Figure 1, and the data are summarized in Figure 2. The distribution of the CAG repeat lengths did not follow the normal distribution. The CAG repeat number was 23.4 ± 0.48 (mean ± SE) (range 16–32, median 23) for the patients with cryptorchidism and 23.5 ± 0.29 (range 15-32, median 23) for control subjects. The difference was not statistically significant between patients and controls. The CAG repeat number was 23.7 ± 0.64 (range 18–32, median 24) for the 31 patients with unilateral cryptorchidism, and 23.8 ± 0.69 (range 16–28, median 23) for the 17 patients with bilateral cryptorchidism; there was no significant difference between the two groups. Furthermore, two of the 48 patients and five of the 100 normal males had the long CAG repeat of ≥29. Thus, the frequency of long CAG repeat was comparable between the cryptorchid patients and the normal males. Discussion It is generally accepted that endocrine factors somehow play a major role in promoting the descent of the testes into the scrotum (Levy and Husmann, 1995). According to Hutson (1986), there are two stages of testicular descent. In the first stage, which may be controlled by Müllerian inhibiting substance (MIS), the testes migrate down towards the lower abdominal wall and reach the site of the future internal inguinal ring by the 7th month. In the second stage, the testes transit the abdominal wall via the inguinal canal and complete their passage into the bottom of the scrotum during the 28th week. Thus, the intra-abdominal portion of testicular descent is not androgen-mediated but the presence of functional androgens and AR is required for the testes to descend through the inguinal canal into the scrotum. In the present study, the size of the CAG repeat in exon 1 of the AR gene did not differ between patients with cryptorchidism and control males. This suggests that expansion of the CAG repeat tracts is unlikely to constitute a major cause of cryptorchidism. In addition, genetic analysis of isolated cryptorchid patients revealed no abnormalities of the coding sequences of exons 2 to 8 of the AR gene (Wiener et al., 1998). Although point mutations in the DNA and ligand domains of the AR are considered as a potential cause of cryptorchidism, these findings imply that the relevance of AR gene alterations to the development of isolated cryptorchidism is rare. It is well known that the size of the CAG repeat in exon 1 of the AR gene varies in a race-specific manner. A study from the USA has shown that the CAG repeat length in black men is significantly shorter than in non-Hispanic white men (Sartor et al., 1999). The prevalence of fewer than 22 CAG repeats was shown to be high in African Americans and low in Asians (Irvine et al., 1995). Furthermore, Chinese patients with defective spermatogenesis show expansion of the CAG repeats in the AR gene (Tut et al., 1997; Yong et al., 1998). Yoshida et al. (1999) also reported that Japanese males with idiopathic azoospermia have significantly longer CAG repeats than fertile Japanese males. In contrast, the size of the CAG repeat in the AR gene shows no significant relationship to impaired spermatogenesis in an infertile Caucasoid sample of German origin and a Swedish population of infertile patients (Giwercman et al., 1998; Dadze et al., 2000). The variability of the results by various investigators may be due to attributes of the different genetic origins of the populations studied (Yoshida et al., 1999; Dadze et al., 2000). In summary, the results imply that the CAG repeat tracts are unlikely to be expanded in patients with cryptorchidism. However, since the relevance of expanded CAG repeat tracts to the development of cryptorchidism remains possible in other patient populations, further studies are required to draw final conclusions on the relevance of CAG repeat length expansion to cryptorchidism. Figure 1. View largeDownload slide The CAG repeat length analysis by GeneScan (above) and direct sequencing (below) in two individuals with short (n = 18) and long (n = 31) CAG repeats. The short and long polymerase chain reaction (PCR) products are estimated as 263 bp and 299 bp in size, respectively, by the GeneScan analysis, and are shown to be 276 bp with 18 CAG repeats and 315 bp with 31 CAG repeats in size, respectively, by the direct sequencing. Because of the discrepancy inherent to GeneScan analysis, it is necessary to sequence each of PCR products with different sizes on GeneScan analysis. Figure 1. View largeDownload slide The CAG repeat length analysis by GeneScan (above) and direct sequencing (below) in two individuals with short (n = 18) and long (n = 31) CAG repeats. The short and long polymerase chain reaction (PCR) products are estimated as 263 bp and 299 bp in size, respectively, by the GeneScan analysis, and are shown to be 276 bp with 18 CAG repeats and 315 bp with 31 CAG repeats in size, respectively, by the direct sequencing. Because of the discrepancy inherent to GeneScan analysis, it is necessary to sequence each of PCR products with different sizes on GeneScan analysis. Figure 2. View largeDownload slide Distribution of the CAG repeat lengths in the controls (closed column) and cryptorchid patients (open column). Figure 2. View largeDownload slide Distribution of the CAG repeat lengths in the controls (closed column) and cryptorchid patients (open column). 3 To whom correspondence should be addressed at: Department of Urology, Yamagata University School of Medicine, 2-2-2 Iidanishi, Yamagata-shi, Yamagata 990-9585, Japan. E-mail: isasaga@med.id.yamagata-u.ac.jp References Allen, R.C., Zoghbi, H.Y., Moseley, A.B. et al. ( 1992) Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlated with X chromosome inactivation. Am. J. Hum. Genet. , 51, 1229–1239. Google Scholar Chamberlain, N.L., Driver, E.D. and Miesfeld, R.L. ( 1994) The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res. , 122, 3181-3186. Google Scholar Dadze, S., Wieland, C., Jakubiczka, S. et al. ( 2000) The size of the CAG repeat in exon 1 of the androgen receptor gene shows no significant relationship to impaired spematogenesis in an infertile Caucasoid sample of German origin. Mol. Hum. Reprod. , 6, 207–214. Google Scholar Dowsing, A.T., Yong, E.L., Clark, M. et al. ( 1999) Linkage between male infertility and trinucleotide repeat expansion in the androgen-receptor gene. Lancet , 354, 640–643. Google Scholar Giovannucci, E., Stampfer, M.J., Krithivas, K. et al. ( 1997) The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. Proc. Natl Acad. Sci. USA , 94, 3320–3323. Google Scholar Giwercman, Y.L., Xu, C., Arver, S. et al. ( 1998) No association between the androgen receptor gene CAG repeat and impaired sperm production in Swedish men. Clin. Genet. , 54, 435–436. Google Scholar Gottlieb, B., Lehvaslaiho, H., Beitel, L.K. et al. ( 1998) The androgen receptor gene mutations database. Nucleic Acids Res. , 26, 234–238. Google Scholar Hardy, D.O., Scher, H.I., Bogenreider, T. et al. ( 1996) Androgen receptor CAG repeat lengths in prostate cancer: correlation with age of onset. J. Clin. Endocrinol. Metab. , 81, 4400–4405. Google Scholar Hutson, J.M. ( 1986) Testicular feminization. A model for testicular descent in mice and men. J. Pediatr. Surg. , 21, 195–198. Google Scholar Irvine, R.A., Yu, M.C., Ross, R.K. and Coetzee, G.A. ( 1995) The CAG and GGC microsatellites of the androgen receptor gene are in linkage disequilibrium in men with prostate cancer. Cancer Res. , 55, 1937–1940. Google Scholar La Spada, A.R., Wilson, E.M., Lubahn, D.B. et al. ( 1991) Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature , 352, 77–79. Google Scholar Levy, J.B. and Husmann, D.A. ( 1995) The hormonal control of testicular descent. J. Androl. , 16, 459–463. Google Scholar Lubahn, D.B., Joseph, D.R., Sullivan, P.M. et al. ( 1988) Cloning of human androgen receptor complementary DNA and localisation of the X chromosome. Science , 240, 327–330. Google Scholar Lubahn, D.B., Brown, T.R., Simental, J.A. et al. ( 1989) Sequence of the intron/exon junctions of the coding region of the human androgen receptor gene and identification of a point mutation in a family with complete androgen insensitivity. Proc. Natl Acad. Sci. USA , 86, 9534–9538. Google Scholar Sartor, O., Zheng, Q. and Eastham, J.A. ( 1999) Androgen receptor gene CAG repeat length varies in a race-specific fashion in men without prostate cancer. Urology , 53, 378–380. Google Scholar Tut, T.G., Ghadessy, F., Trifiro, M.A. et al. ( 1997) Long glutamine tracts in the androgen receptor are associated with reduced transactivation, impaired sperm production and male infertility. J. Clin. Endocrinol. Metab. , 82, 3777–3782. Google Scholar Quigley, C.A., De Bellis, A., Marschke, K.B. et al. ( 1995) Androgen receptor defects: historical, clinical and molecular perspectives. Endocr. Rev. , 16, 271–321. Google Scholar Wiener, J.S., Teague, J.L., Roth, D.R. et al. ( 1997) Molecular biology and function of the androgen receptor in genital development. J. Urol. , 157, 1377–1386. Google Scholar Wiener, J.S., Marcelli, M., Gonzales, E.T. Jr et al. ( 1998) Androgen receptor gene alterations are not associated with isolated cryptorchidism. J. Urol. , 160, 863–865. Google Scholar Yong, E.L., Ghadessy, F., Wang, Q. et al. ( 1998) Androgen receptor transactivation domain and control of spermatogenesis. Rev. Reprod ., 3, 141–144. Google Scholar Yoshida, K., Yano, M., Chiba, K. et al. ( 1999) CAG repeat length in the androgen receptor gene is enhanced in patients with idiopathic azoospermia. Urology , 54, 1078–1081. Google Scholar © European Society of Human Reproduction and Embryology

Journal

Molecular Human ReproductionOxford University Press

Published: Nov 1, 2000

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