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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 5 1590-1594
Copyright © 1999 by The Endocrine Society

From the Clinical Research Centers

A Novel Mutation in the CAG Triplet Region of Exon 1 of Androgen Receptor Gene Causes Complete Androgen Insensitivity Syndrome in a Large Kindred1

Yuan-Shan Zhu, Li-Qun Cai, Juan J. Cordero, William J. Canovatchel, Melissa D. Katz and Julianne Imperato-McGinley

Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cornell University Medical College, New York, New York 10021.

Address all correspondence and requests for reprints to: Dr. Julianne Imperato-McGinley, Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, New York Hospital-Cornell Medical Center, 1300 York Avenue, Box-149, Room F-263, New York, New York 10021. E-mail: jimperat{at}mail.med.cornell.edu


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Complete androgen insensitivity syndrome (CAIS) is an X-linked inherited disease caused by mutations in the androgen receptor (AR) gene. We have previously reported the largest kindred of CAIS, with 17 46,XY psychosexual and phenotypic females who lack secondary sexual hair. Analysis of AR binding indicated a receptor-negative form of complete androgen insensitivity, and DNA linkage analysis indicated that the absent binding was not caused by a large AR gene deletion. Using PCR-single-strand DNA conformational polymorphism, PCR-denaturing gradient gel electrophoresis, and DNA sequencing, we have identified a novel mutation in the polymorphic CAG trinucleotide region of exon 1 of the AR gene, where a single adenine is inserted, or equivalently, a GC-dinucleotide is deleted at this region of the gene. The mutation results in a frameshift at amino acid 60 and a premature termination of the receptor downstream of the mutation. This predicts a mutant AR with only 79 amino acids in the amino-terminal of AR protein, prohibiting binding to the ligand, as well as the cognate DNA. The rest of the encoding regions of the AR gene in the affected subjects are normal. These results are consistent with previous ligand binding and DNA linkage analysis studies. This new mutation in the CAG trinucleotide area of exon 1 of the AR gene represents the first example of a defect in a CAG repeat causing CAIS in this large kindred. All previous reported variants in this region are changes in the number of triplet repeats.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE COMPLETE androgen insensitivity syndrome (CAIS), or testicular feminization, is a form of male pseudohermaphroditism caused by defects in the androgen receptor (AR) (1, 2). Subjects with CAIS, despite a 46,XY karyotype, testes, and normal-to-elevated plasma levels of testosterone, have female external genitalia and female psychosexual orientation (1, 2, 3, 4). At puberty, breast development occurs with scant-to-absent pubic and axillary hair. Partial forms of androgen insensitivity also occur with a broad spectrum of phenotypes, from females with clitoromegaly, to males with hypospadias and/or micropenis, to males with infertility or gynecomastia in its mildest forms (1, 2).

The AR is a member of the nuclear steroid receptor superfamily (2, 5). It consists of 910–919 amino acids and is encoded by a gene with 8 exons located in Xq11–12. Like other steroid receptors, the AR is a single polypeptide comprised of relatively distinct domains: an amino-terminal domain, a DNA binding domain, a hinge region, and a steroid-binding domain. The large amino-terminal domain encoded by exon 1 is the least conserved region among the steroid receptors and is involved in transcriptional activation of target genes. The DNA binding domain encoded by exon 2 and 3 contains two zinc finger motifs (6) and is the most highly conserved region and is responsible for specific binding to its cognate DNA, i.e. androgen response element of target genes. The carboxyl-terminal of the AR contains the steroid-binding domain, encoded by the 3' portion of exon 4, and exons 5–8. It is responsible for the specific high-affinity ligand binding. The carboxyl-terminal region also contains the subdomains involved in dimerization and transcriptional activation (7, 8, 9). Between the DNA-binding domain and the steroid-binding domain is the hinge region, which is encoded by the 5' portion of exon 4 and which contains the nuclear translocation signal (7, 8).

We have previously reported the largest known kindred with complete androgen insensitivity (1, 3, 10), consisting of 17 affected subjects (Fig. 1Go). The clinical phenotype and the hormone profiles of the affected subjects from this kindred were previously published (3). Pedigree analysis (Fig. 1Go) demonstrated a maternal transmission, with the defect manifested in the fourth, fifth and sixth generations. Plasma testosterone levels were high normal or elevated. Dihydrotestosterone (DHT) levels were decreased and the ratio of testosterone/DHT elevated, as a consequence of a secondary 5{alpha}-reductase deficiency caused by androgen resistance (3). Analysis of AR binding in genital skin fibroblasts from CAIS subjects demonstrated a complete absence of receptor binding (3). DNA linkage analysis indicated that the absence of receptor binding was not caused by an entire AR gene deletion (10).



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  		Figure 1. Pedigree of a large kindred with CAIS. Circles and squares indicate females and males, respectively. The Roman numerals indicate the generation. Solid circles indicate the affected CAIS subjects. The asterisks indicate the affected CAIS subjects analyzed in the present study.

 
In the present study, we identified the genetic defect responsible for complete androgen insensitivity in this large kindred. It is a novel mutation in the polymorphic CAG trinucleotide region of exon 1 of the AR gene, resulting in a frameshift and consequently premature termination of the AR in exon 1.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
PCR amplification of the AR gene

Peripheral blood was drawn from two affected subjects (indicated by an asterisk in Fig. 1Go), into EDTA-containing tubes; and genomic DNA from white blood cells was isolated by a genomic DNA isolation kit (Qiagen, Chatsworth, CA), according to the manufacture’s instruction. The concentrations of DNA were determined by ultraviolet absorbance. This study was approved by the Institutional Review Board of Cornell University Medical College. Exons 1–8 of the AR gene (11, 12) were amplified by PCR using primers and conditions shown in Table 1Go. Six sets of inner primers were used for exon 1. The reaction mixture contained 0.18 µg genomic DNA, 200 µmol/L of each of four deoxyribonucleotide triphosphates, 10 mmol/L Tris-HCl (pH 8.3), 50 mmol/L KCl, 0.1% Triton X-100, 2.5 U thermostable DNA polymerase (Promega Corp., Madison, WI), and the amounts of primers and MgCl indicated in Table 1Go. For hot PCR, 10 µCi [{alpha}-32P]deoxy-ATP was added. The samples were denatured at 95 C for 2 min and then sequentially denatured at 95 C for 15 sec, annealed at the temperature shown in Table 1Go for 30 sec, and extended at 72 C for 30 sec for a total of 35 cycles. A final extension cycle consisted of 72 C for 10 min.


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  		Table 1. Primer sequences and PCR conditions for the amplification of AR gene

 
Single-strand DNA conformational polymorphism (SSCP) analysis and denaturing gradient gel electrophoresis (DGGE)

SSCP analysis was performed as described earlier (13, 14). Briefly, exon DNA was amplified and radiolabeled as described above. One microliter of the PCR product was added to 9 µL formamide denaturing dye (98% formamide, 20 mmol/L EDTA, 10 mmol/L NaOH, and 0.05% each of xylene cyanol and bromophenol blue), denatured at 100 C for 6 min and immediately cooled on ice. Three microliters of this solution were loaded onto a 0.5 x Hydrolink MDE gel (J. T. Baker Inc., Phillipsburg, NJ), containing 10% glycerol, and electrophoresed at 350 V at room temperature overnight in 0.6 x TBE buffer (54 mmol/L Tris-borate (pH 8.3) and 2.4 mmol/L EDTA). An aliquot of hot PCR sample, without denaturation, was loaded in an adjacent lane to determine the position of migration of the double-stranded DNA fragment. After electrophoresis, the gel was dried and exposed to Kodak BioMAX film (Eastman Kodak Co., Rochester, NY) at room temperature.

For DGGE, GC-clamp primers were synthesized for exons 4–8 of the AR gene, and PCR amplification was carried out as described above. Amplified DNA fragments were denatured at 95 C for 10 min and reannealed by cooling down slowly to room temperature, and electrophoresed in an 8% denaturing gradient polyacrylamide (19:1 acrylamide:bisacrylamide) gel in 0.5 x TBE buffer. The 100% denaturant was 7 mol/L urea plus formamide (60:40 by vol). Intermediate denaturants were prepared by diluting 100% denaturant with 8% acrylamide in 0.5 x TBE. Gradients were prepared bottom-up by gravity flow in a gradient maker. A Miniprotein apparatus (Bio-Rad Laboratories, Hercules, CA.) with 1.5 mm spacers was used for all of the experiments. The results were visualized by ethidium bromide staining, as described previously (15, 16).

DNA sequencing

DNA fragments of the AR gene were amplified by PCR, as described above. The PCR product was purified by PAGE (17). The concentration of purified DNA fragment was estimated using DNA QuikSTRIP (Eastman Kodak Co.). DNA sequencing was carried out using fmol DNA sequencing kit (Promega Corp.) with 32P end-labeled primer (13, 14). Both strands of DNA were sequenced.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
To identify the genetic defect in these CAIS subjects, genomic DNA was isolated from the white blood cells of 2 affected CAIS subjects (indicated by an asterisk in Fig. 1Go). The entire encoding region of the AR gene was amplified by PCR using the primers and conditions shown in Table 1Go. The exon 1 coding sequence was amplified with 6 pairs of overlapping primers. Using SSCP analysis, all 8 exons of the AR gene were screened for a mutation. Figure 2Go shows a representative SSCP analysis of the 5' portion of exon 1 of the AR gene, which demonstrates a differential migration pattern of the single-stranded DNA in the affected CAIS subject, compared with the normal control. This differential migration pattern results from either a potential mutation in this region or a difference in the size of CAG trinucleotide repeats of the AR gene. DNA sequencing (Fig. 3AGo) of this putative mutant fragment identified a novel mutation in the polymorphic CAG trinucleotide repeats of exon 1 of the AR gene in the affected CAIS subjects (see Fig. 3Go), where either a single adenine (A) is inserted between nucleotide position 179 and 180 (... 178CAAGCAG183... ), or alternatively, a GC-dinucleotide is deleted at nucleotide positions 180 and 181 (... 178CAGCAG183... ) of the AR gene (base 1 starts at the first nucleotide of the translation start codon of the AR gene, and all nucleotide and amino acid position numbers referred to in this paper are according to human AR complementary DNA in GenBank accession no. M20132). Either mutation would result in a frameshift at amino acid position 60 and an introduction of premature stop codons in exon 1 of the AR gene. Thus, the predicted mutant AR is a truncated protein with only 79 amino acids at the amino-terminal (see Fig. 3BGo).



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  		Figure 2. A representative SSCP analysis of a 5' portion of exon 1 of the AR gene. Hot PCR amplification was done using primers AR1N and AR1C1 and then analyzed by SSCP, as described in Materials and Methods. The bands on the top represent the mobility of various single-strand DNA conformations, and the band on the bottom is the double-stranded DNA, as indicated by an arrowhead.

 


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  		Figure 3. The identification of a novel new mutation in exon 1 of AR gene in the affected CAIS subjects from a large kindred. Panel A shows a representative DNA sequencing of a 5' portion of exon 1 of the AR gene. The fragment was amplified by PCR using primers AR1N and AR1C1, purified by polyacrylamide gel and sequenced using 32P end-labeled AR1C1 primer, as described in Materials and Methods. The solid arrowheads indicate the insertion of an adenine (A) in the normal sequence. The sequences on both sides are read from top to bottom as 5' to 3'. Panel B shows partial nucleotide and amino acid sequences of exon 1 of human AR to illustrate the single base (adenine) insertion (indicated by a bold and underlined A), or a GC-dinucleotide deletion in the exon 1 of AR gene. This mutation results in a frameshift at amino acid position 60 and an abnormal premature termination at codon 80 (TAG). The sequences after the mutation are indicated as italic letters. Panel C shows the genomic structure and the corresponding encoded functional domains of the human AR gene. The exons are indicated by boxes and introns by dashed lines. The shaded boxes indicate the coding region and the open boxes indicate the untranslated regions. The currently identified mutation within the polymorphic CAG trinucleotide repeats is indicated by a big bolded A and an arrow for a single base (adenine) insertion or by the underlined GC for the alternative GC-dinucleotide deletion.

 
The remainder of the encoding region of the AR gene in the affected subjects was normal by SSCP analysis and DNA sequencing. Exons 4–8 were also screened by DGGE, and no mutation was detected (data not shown).

The identified mutation in the CAG triplet repeats of exon 1 of the AR gene was not detected in a normal 46,XY brother, suggesting that this new mutation is responsible for complete androgen insensitivity in this large pedigree.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We have previously reported and characterized the largest known kindred with CAIS in the world (3, 10). In the present study, a new and novel mutation of the AR gene is identified as the genetic defect in this kindred (see Fig. 3Go). A single base, adenine (A), is inserted between nucleotide position 179 and 180 (nucleotide position no. 1 starts at the translation start codon) in the polymorphic CAG trinucleotide region of exon 1. Alternatively, because of the presence of the polymorphic CAG trinucleotide repeats, the defect could also be attributable to a GC-dinucleotide deletion at positions 180–181 of exon 1 of the AR gene (see Fig. 3Go). The precise mutation in the sequence is ambiguous. However, either an adenine insertion or a GC-dinucleotide deletion yields a frameshift at amino acid 60, introducing a premature termination codon downstream from the mutation, predicting the synthesis of a truncated protein with only 79 amino acids in the amino-terminal and all functional domains absent (see Fig. 3Go, B and C). The rest of the exon sequences and splicing junctions of the AR gene in the affected subjects were normal, by DNA sequencing, SSCP, and DGGE analysis. The identified mutation was not detected in a normal 46,XY sibling.

Our previous studies of affected subjects from this pedigree demonstrated absent DHT-binding in genital skin (3), consistent with the fact that a ligand-binding domain is absent in the mutant receptor. Also, a large deletion of the AR gene was not detected by previous studies of DNA linkage analysis (10), because of the fact that only a single base insertion is present in exon 1. Because this mutation leads to the synthesis of a nonfunctional truncated AR fragment in the affected subjects, it is not surprising that affected subjects from this kindred present with the phenotype of complete androgen insensitivity.

Different frameshift mutations in exon 1 of the AR gene have been previously reported by others, in affected CAIS subjects (2, 18, 19) and in the Tfm mouse (20). It has been shown that in the Tfm mouse, reinitiation of protein translation from an internal methionine codon downstream of the abnormal premature stop codon produces a low level of truncated receptor (20), containing both the DNA binding domain and the ligand binding domain. This explains why a small amount of DNA binding and androgen binding activity is detected in Tfm mice (21). A similar phenomenon has been reported in CAIS affected subjects with a nonsense mutation (CAG->TAG) at amino acid position 60 (Q60stop) of exon 1 of the AR gene (22). Reinitiation of AR translation distal to the abnormal stop codon results in synthesis of a small amount of truncated AR and a low level of androgen binding activity. This truncated AR is named as an A form of AR, and has recently been shown to possess similar functional activities as the wild-type, B form (23). Theoretically, reinitiation of AR translation downstream of the mutation could also occur in our currently identified mutation. However, because we did not detect any AR binding activity in the genital skin fibroblasts from the CAIS affected subjects of this kindred (3), it is likely that the reinitiation of truncated AR translation is either absent or negligible. Although reinitiation of truncated AR translation has been reported (20, 21, 22), most AR exon 1 mutations identified in CAIS subjects did not report downstream reinitiation. The reason for this difference is unclear. Translation efficiency may be one explanation, as McPhaul’s group reported that the replacement of the upstream sequences of the translation reinitiation site by the upstream sequences of the normal translation initiation site could significantly increase mutant receptor expression (23).

To date, more than 245 different mutations, involving all 8 exons in the AR gene, have been reported (2, 19). These mutations range from a single point mutation to an entire gene deletion and result in various degrees of functional impairment of the AR and a wide phenotypic spectrum of the syndrome of androgen insensitivity. However, there is no consistent relationship between the clinical phenotypes and the molecular defects in the AR gene. Most of the reported mutations are single point missense mutations located in exons 2–8 of the AR gene. Interestingly, mutations in exon 1 of the AR gene are found less frequently than found in other exons. Seventeen mutations of exon 1 have been reported in androgen insensitivity. Six are attributable to small deletions or insertions (2, 19), resulting in CAIS. The other mutations include 8 nonsense and 3 missense mutations.

Our reported mutation has never been previously reported. It is unique in terms of its location within the region of polymorphic CAG trinucleotide repeats of exon 1 and its feature as either a single adenine insertion or a GC-dinucleotide deletion (see Fig. 3Go). The region of CAG triplet repeats in exon 1 of the AR gene is genetically unstable, and this instability is greater in male than in female meiosis (2). An increase in CAG repeats in this region is associated with Kennedy disease, i.e. X-linked spinal and bulbar muscular atrophy (2, 24). A shortening of the number of CAG repeats may also be related to prostate cancer risk (25). Thus, all previously reported variants in this region are variations in the numbers of triplet repeats. Our currently reported mutation represents the first example of small insertion or deletion in this CAG triplet region. The mechanism of this genetic instability is unclear, although slippage of DNA polymerase during DNA replication is possible (2).

In summary, we have identified a novel new mutation in exon 1 of the AR gene, responsible for the CAIS in the largest known kindred with this syndrome in the world.


   Footnotes
 
1 This work was supported, in part, by NIH Grants HD-09421–15 and M01-RR-00047 and by the Merck Foundation. Back

Received August 31, 1998.

Revised February 3, 1999.

Accepted February 9, 1999.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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