CAG Repeat In Exon Research Articles

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

We analysed the CAG repeat length in exon 1 of the androgen receptor gene in 59 idiopathic Japanese infertile males with oligozoospermia; 36 fertile males were also analysed as controls. The number of CAG repeats in infertile males ranged from 14 to 32 (mean 21.2+/-4.2), whereas the number of CAG repeats in fertile males ranged from 16 to 31 (mean 21.4+/-3.5). Among infertile males, six possessed a short form of 14 CAG repeats and three possessed 15 CAG repeats. On the other hand, fertile males did not possess the short form of 14 or 15 CAG repeats. The incidence of infertile males with 14 and 15 CAG repeats was significantly higher (P<0.05) than that of fertile males. Although the sample size is small, the results suggest that the reduction of CAG repeats in exon 1 of the androgen receptor is closely related to impaired spermatogenesis in infertile Japanese males.

Striatal transplantation in a transgenic mouse model of Huntington's disease.

Striatal grafts have been proposed as a potential strategy for striatal repair in Huntington's disease, but it is unknown whether the diseased brain will compromise graft survival. A transgenic mouse line has recently been described in which hemizygotes with an expanded CAG repeat in exon 1 of the HD gene exhibit a progressive neurological phenotype similar to the motor symptoms of Huntington's disease. We have therefore evaluated the effects of the transgenic brain environment on the survival, differentiation, and function of intrastriatal striatal grafts and undertaken a preliminary analysis of the effects of the grafts on the development of neurological deficits in the host mice. Hemizygote transgenic and wild-type littermate female mice received striatal grafts at 10 weeks of age and were allowed to survive 6 weeks. Normal healthy grafts were seen to survive and differentiate within the striatum of transgenic mice in a manner comparable to that seen in control mice. The transgenic mice exhibited a progressive decline in body weight from 9 weeks of age and a progressive hypoactivity in an open field test of general locomotor behavior. Although striatal grafts exerted a statistically significant influence on several indices of this impairment, all behavioral effects were small and did not exert any clinically relevant effect on the profound neurological deficiency of the transgenic mice.

Genetic alterations of androgen receptor gene in Japanese human prostate cancer.

In order to determine the significance of androgen receptor (AR) gene mutations for Japanese prostate cancers, we examined the entire coding region, from exon A to H, in 36 primary lesions. Five in stage A, 12 in stage B, six in stage C and 13 in stage D were subjected to PCR-SSCP analysis for genomic DNA and nucleotide sequencing. Mutations were detected in five samples (14%). Two in stage D and refractory to anti-androgen treatment showed mis-sense mutations. The other three showed changes in the length of the CAG repeat in exon A, with an expansion or a contraction of one repeat unit. However, no association with changes in AR function was indicated because they had not been refractory to hormone therapy. Since these latter three tumors were associated with microsatellite instability, the changes might have been the result of an impairment of mismatch repair. This study indicates that AR gene mutations play a role, in only a subset of prostate cancer patients, in a treatment-refractory state.

Determination of cag repeat length in the androgen-receptor gene using frozen serum

Objectives To determine CAG repeat length in exon one of the androgen-receptor gene, using frozen serum as a source of deoxyribonucleic acid (DNA). Methods Samples from previously frozen serum samples were prepared for polymerase chain reaction (PCR) by heating thawed serum to 100 °C and subsequent centrifugation at 16,000 g. Three microliters of supernatant were added to the PCR in combination with primers flanking the CAG repeat in exon one of the human androgen-receptor gene. After 35 cycles, the PCR amplicons were electrophoresed on an agarose gel, excised, purified, and sequenced. CAG repeat length was directly determined from DNA sequencing gels. Results Amplified DNA fragments were obtained after PCR from 140 of the 200 specimens examined to date. The DNA amplicon was successfully sequenced in 111 samples derived from 104 individuals. Within this group, the androgen receptor CAG repeat length varied from 11 to 27. The median CAG repeat length was 21 ; the lower and upper quartiles were 18 or less and 23 or more, respectively. Results were consistent in each case that CAG repeat length was repetitively determined. Conclusions The establishment of a methodology to determine androgen-receptor gene CAG repeat length from frozen serum samples opens multiple new opportunities to explore the potential clinical significance of this genetic polymorphism.

Spinal and bulbar muscular atrophy: androgen receptor dysfunction caused by a trinucleotide repeat expansion

Kennedy's disease (spinal and bulbar muscular atrophy) is an X-linked form of motor neuron disease that affects adult men. The syndrome is characterized by progressive atrophy of the limb muscles, pelvic and shoulder girdles and dysphagia and dysarthria, and is caused by the degeneration of spinal and bulbar motor neurons. Kennedy's disease is caused by a trinucleotide repeat expansion of a CAG repeat in exon A of the androgen receptor gene, and is one of a group of neurological diseases caused by trinucleotide repeat expansions in different genes. The mutation in Kennedy's disease involves an increased number of glutamine residues in the amino-terminal domain of the receptor. Point mutations and deletions in the androgen receptor gene cause androgen insensitivity syndrome, however subjects with Kennedy's disease have normal virilization, although progressive gynaecomastia, testicular atrophy and infertility may occur. Androgen receptors are expressed widely in the normal brain, and in the anterior horn cells of the spinal cord; however, their role in neuronal tissue is not known, nor is it known how the androgen receptor gene mutation causes neuronal degeneration. Kennedy's disease is likely to be a ‘gain of function’ abnormality, so that the presence of the receptor with an increased number of glutamines is toxic to motor neurons. It is possible that the mutation alters interaction of the receptor with other neuronal transcription factors, or neuronotoxicity may occur because of a non-specific effect caused by the presence of a protein with a large homoglutamine domain. Studies of patients with Kennedy's disease have shown that expression of androgen receptor mRNA and protein in spinal cord may be decreased, as can be the affinity of the mutant receptor for androgen. In vitro studies have shown impaired transcription activation ability of the mutant androgen receptor. The age at onset of Kennedy's disease may correlate with the size of the CAG repeat, however there is a large degree of variability of age at onset between subjects with the same number of repeats. Further study of the effect of the Kennedy's disease mutation on androgen receptor function in motor neurons will allow us to increase our understanding of the pathogenesis of this disease.

Strong correlation between the number of CAG repeats in androgen receptor genes and the clinical onset of features of spinal and bulbar muscular atrophy.

X-linked spinal and bulbar muscular atrophy (SBMA), a motor neuron disease associated with androgen insensitivity, is caused by androgen receptor gene mutations with an increased number of tandem CAG repeats in exon 1. We investigated the increased number of CAG repeats in androgen receptor genes of 19 SBMA patients and found that this correlated strongly with the age at onset of muscle weakness. Thus, SBMA is the first genetic disease in which a strong correlation between the degree of genetic abnormality (number of CAG tandem repeats) and clinical phenotypic expression is demonstrable. The results further indicate that androgen gene mutation is directly involved in the degeneration of motor neurons.