Effect of CAG repeats on the age at onset of patients with spinocerebellar ataxia type 2 in China / 中南大学学报(医学版)

Objective: Spinocerebellar ataxia type 2 (SCA2) is one of the most common autosomal dominant ataxias in the world. Several reports revealed that CAG repeats in some polyQ-containing genes may affect the age at onset (AAO) of patients with SCA2, however, little studies were conducted among Chinese patients with SCA2. Thus, the aim of this study is to evaluate the effect of CAG repeats on the AAO of patients with SCA2 in China.Methods:A total of 119 patients with SCA2 were enrolled and were divided into 2 groups according to their major phenotype:17 patients from 9 families with Parkinson ' s syndrome were grouped as the Parkinson ' s disease-SCA2 (PD-SAC2); 91 patients from 66 SCA2 families and 11 sporadic SCA2 patients were grouped as the ataxia-SCA2 (A-SCA2). Blood samples were obtained from the subjects, and the CAG repeat length in ATXN2 and other (CAG)n-containing genes was screened using fluorescent PCR. The Spearman ' s rank correlation between the CAG repeat length in (CAG)n-containing genes and AAO was analyzed. Regression analysis was performed to investigate whether the CAG repeat length could explain the variant of AAO. A t-test was used to compare the difference of CAG repeat length in (CAG)n-containing genes between the PD-SAC2 and A-SCA2 groups. Results:The CAG repeat length in the longer allele of ATXN2 was negatively correlated with AAO of SCA2 (R=?0.251, P<0.05), and the CAG repeat length could explain 41.7％of the variation of AAO. AAO negatively correlated with the CAG repeat length in the shorter allele of ATXN7 (R=?0.251, P=0.006) or in the longer allele of TBP gene (R=?0.197, P=0.034). A tendency of delay in the AAO was also observed in patients with SCA2 carrying the CAG repeat within the ATXN3, CACNA1A, ATXN7, TBP, and RAI1. In addition, we found that the CAG repeat length in ATXN7 and ATXN2 between the A-SCA2 and the PD-SCA2 groups was significantly different (both P<0.05).Conclusion:The CAG repeat in ATXN2 is a major genetic factor for the AAO of patients with SCA2 in China. The CAG repeat length in ATXN3, CACNA1A, ATXN7, TBP, and RAI1 genes might be a potential factor associated with the AAO of SCA2. The CAG repeat in ATXN7 might be a potential factor affecting the Parkinson??s syndrome in SCA2.

Polymorphisms in the androgen receptor CAG repeat sequence are related to tumour stage but not to ERG or androgen receptor expression in Malaysian men with prostate cancer

@#Introduction: Polymorphic expression of a CAG repeat sequence in the androgen receptor (AR) gene may influence the activity of the AR and the occurrence of prostate cancer and the TMPRSS2-ERG fusion event. Furthermore, this polymorphism may be responsible for the ethnic variation observed in prostate cancer occurrence and expression of the ERG oncogene. We investigate the expression of AR and ERG in the biopsies of Malaysian men with prostate cancer and in the same patients relate this to the length of the CAG repeat sequence in their AR gene. Materials and Methods: From a PSA screening initiative, 161 men were shown to have elevated PSA levels in their blood and underwent prostatic tissue biopsy. DNA was extracted from the blood, and exon 1 of the AR gene amplified by PCR and sequenced. The number of CAG repeat sequences were counted and compared to the immunohistochemical expression of ERG and AR in the matched tumour biopsies. Results: Of men with elevated PSA, 89 were diagnosed with prostate cancer, and 72 with benign prostatic hyperplasia (BPH). There was no significant difference in the length of the CAG repeat in men with prostate cancer and BPH. The CAG repeat length was not associated with; age, PSA or tumour grade, though a longer CAG repeat was associated with tumour stage. ERG and AR were expressed in 36% and 86% of the cancers, respectively. There was no significant association between CAG repeat length and ERG or AR expression. However, there was a significant inverse relationship between ERG and AR expression. In addition, a significantly great proportion of Indian men had ERG positive tumours, compared to men of Malay or Chinese descent. Conclusions: CAG repeat length is not associated with prostate cancer or expression of ERG or AR. However, ERG appears to be more common in the prostate cancers of Malaysian Indian men than in the prostate cancers of other Malaysian ethnicities and its expression in this study was inversely related to AR expression.

Evaluating the current state of the art of Huntington disease research: a scientometric analysis

Huntington disease (HD) is an incurable neurodegenerative disorder caused by a dominant mutation on the 4th chromosome. We aim to present a scientometric analysis of the extant scientific undertakings devoted to better understanding HD. Therefore, a quantitative study was performed to examine the current state-of-the-art approaches that foster researchers' understandings of the current knowledge, research trends, and research gaps regarding this disorder. We performed literature searches of articles that were published up to September 2016 in the "ISI Web of Science™" (http://apps.webofknowledge.com/). The keyword used was "Huntington disease". Of the initial 14,036 articles that were obtained, 7732 were eligible for inclusion in the study according to their relevance. Data were classified according to language, country of publication, year, and area of concentration. The country leader regarding the number of studies published on HD is the United States, accounting for nearly 30% of all publications, followed by England and Germany, who have published 10 and 7% of all publications, respectively. Regarding the language in which the articles were written, 98% of publications were in English. The first publication to be found on HD was published in 1974. A surge of publications on HD can be seen from 1996 onward. In relation to the various knowledge areas that emerged, most publications were in the fields of neuroscience and neurology, likely because HD is a neurodegenerative disorder. Publications written in areas such as psychiatry, genetics, and molecular biology also predominated.

Implicancias del polimorfismo de repeticiones de glutamina del receptor de andrógenos en la presentación de eventos peripuberales / Implications of androgen receptor gene glutamine repeat polymorphism in the presentation of peripubertal events

Puberty is a period of transition during which girls and boys acquire secondary sexual characteristics and reproductive capacity. The order of appearance of the pubertal traits accounts for a correct or otherwise incorrect activation of the hypothalamic-pituitary-gonadal axis. The growth of the pubic hair before 8 years in girls and 9 years in boys (precocious pubarche, PP) without any other apparent cause has been largely attributed to the early increase of adrenal androgen levels. Also, premature adrenarche (PA) was traditionally considered an extreme within the normal range, however emerging evidence links early androgen excess with the metabolic syndrome. In this context, it has been suggested that an exacerbated clinical manifestation of androgens may be related to greater sensitivity of the androgen receptor (AR). The purpose of this review is to summarize the current knowledge of the contribution of the CAG repeats polymorphisms of AR in the peripubertal manifestations of androgens with special emphasis on precocious pubarche and body composition

Related research of male breast cancer and CAG repeat polymorphism of AR gene / 实用肿瘤学杂志

Objectiv e To investigate the correlation between ( CAG) n repeat polymorphism of androgen receptor(AR)geneandmalebreastcancer.Methods 40casesofmalebreastcancerand40controlswerecol-lected.DNA was extracted from peripheral blood and the AR gene CAG coding exon sequences for PCR amplifica -tion,sequencing and calculated the number of CAG repeats frquency .χ2 test and Logistic regression analysis were used assess the AR gene CAG repeat length frequency affect the number of male breast cancer risk .Results There was statistically significant difference in male breast cancer cases and controls the number of CAG repeat length frequency.Man for whom the(CAG)n≥22 repeat sequence had 3.52 times risk of male breast compared (CAG)n≤22(OR=3.52,P=0.036).Conclusion AR gene CAG repeat length is a predictor of the frequency of male breast cancer risk .Longer CAG repeats can increase the risk of male breast cancer .

CAG-Expansion Haplotype Analysis in a Population with a Low Prevalence of Huntington's Disease

BACKGROUND AND PURPOSE: The prevalence of Huntington's disease (HD) among East Asians is less than one-tenth of that among Caucasians. Such a low prevalence may be attributable to a lack of carriers of specific predisposing haplogroups associated with the high instability of the Huntingtin gene (HTT). The aim of this study was to evaluate the association between specific HTT haplogroups and the occurrence of HD in a Thai population. METHODS: CAG-repeat sizes and HTT haplotypes were analyzed in 18 Thai HD patients and 215 control subjects. Twenty-two tagging single-nucleotide polymorphisms (tSNPs) were genotyped. RESULTS: Only 18 patients from 15 unrelated families were identified over the last 17 years. Pathological CAG-repeat alleles ranged from 39 to 48 repeats (43.5+/-3.0, mean+/-SD), and normal alleles ranged from 9 to 24 repeats (16.49+/-1.74). Only two of the chromosomes studied comprised intermediate alleles. Unlike the Caucasian data, all but 1 of the 22 tSNPs were not associated with the occurrence of HD. The predisposing haplogroups for Caucasian HD (haplogroups A1 and A2) are very rare in Thai patients (<4%). Both HD and normal chromosomes are commonly haplogroups A5 and C, in contrast to the case for Chinese and Japanese patients, in whom only haplogroup C was common in HD chromosomes. The frequency of CAG-repeat sizes of haplogroup A5 and C were also similarly distributed. CONCLUSIONS: HD chromosomes of Thai patients may arise randomly from each haplogroup, with a similar mutation rate. This rate is much lower than the CAG expansions from Caucasian HD haplogroups. These data suggest that the different mechanisms underlie CAG expansion in Thai and Caucasian patients.

Germline (CAG) n repeat length of androgen receptor among metastatic prostate cancer patients after endocrine therapy / 中华泌尿外科杂志

Objective To investigate the clinical significance of (CAG)n repeats length of androgen receptor (AR) among the patients with metastatic prostate cancer (TxNxM1),and to analyze their relevance to survival.Methods This study retrospectively investigated fifty-three metastatic prostate cancer patients aged 65 years (range 45-87) who were initially treated with endocrine therapy.The length of the (CAG) n repeats of blood samples was determined by both PCR sequencing and fragment analysis.The clinical significance of (CAG)n repeats and its correlation with biochemical progression free survival (bPFS)and overall survival (OS) were investigated.Results The median length of CAG repeats was 21,ranged from 14 to 32.According to the median (CAG)n repeats length,two groups were divided as (CAG)n ≤ 21and(CAG) n≥ 22.The median follow-up was 36 months.Patients with (CAG)n ≤ 21 had significantly shorter OS and bPFS than those with (CAG)n ≥ 22 (P ＜0.05).Shorter CAG repeats remained significant bPFS (HR 2.820,95％CI 1.466-5.427,P=0.002) and OS (HR 5.245,95％CI 1.293-21.27,P=0.020) predictor in multivariate analysis.Conclusions The efficacy of endocrine therapy for metastatic prostate cancer patients maybe influenced by the AR-CAG repeats length,and short (CAG) n repeats predict bad prognosis.

Relation of CAG Repeat Polymorphism of AR Gene in Men of Han Nationality from Northern China to the Effectiveness of Hypoxic Training / 中国运动医学杂志

Objective To investigate the distribution characteristics of (CAG)n polymorphism in the exonl of the androgen receptor (AR) gene and its relation to the sensitivity of hypoxic training in men of Han nationality from northern China. Methods Sixty five healthy young men of Han nationality completed HiHiLo training under simulated normobaric hypoxic environment for 4 weeks. They stayed under the condition of 14.3-14.8% O_2 (simulating 2800～3000m) during nighttime and carried out hypoxic training under the condition of 14.8-15.4% O_2 (simulating 2500～2800m) 3 times per week at the intensity of 75% individual VO_2max. VO_2max and body weight of the subjects were measured. GeneScan method was used to identify the repeat alleles (genotypes) of CAG polymorphism. Results (1) Fifteen alleles (CAG)12,(CAG)16-28,(CAG)30 repeat alleles (genotypes) were observed in the subjects, in which (CAG)22 was the most common allele; (2) When 21 and 22 alleles were used as the cut point, the baseline of body weight in those carrying shorter genotypes was significantly lower than that in those carrying longer genotypes; (3) △VO_2max and △rVO_2max in men carrying shorter genotypes were significantly higher than that in men carrying longer genotypes after hypoxic training. Conclusion The result reveals that AR (CAG)n polymorphism is associated with the sensitivity of simulated normobaric hypoxic HiHiLo training in men of Han nationality from northern China, especially in those carrying shorter genotypes of AR CAG.

Spinocerebellar ataxia 7 (SCA7)

The autosomal dominant spinocerebellar ataxias (SCAs) are a group of neurodegenerative diseases, clinically and genetically heterogeneous, characterized by degeneration of spinocerebellar pathways with variable involvement of other neural systems. At present, 27 distinct genetic forms of SCAs are known: SCA1-8, SCA10-21, SCA23, SCA25-28, DRPLA (dentatorubral-pallidoluysian atrophy), and 16q-liked ADCA (autosomal dominant cerebellar ataxia). Epidemiological data about the prevalence of SCAs are restricted to a few studies of isolated geographical regions, and most do not reflect the real occurrence of the disease. In general a prevalence of about 0.3-2 cases per 100,000 people is assumed. As SCA are highly heterogeneous, the prevalence of specific subtypes varies between different ethnic and continental populations. Most recent data suggest that SCA3 is the commonest subtype worldwide; SCA1, SCA2, SCA6, SCA7, and SCA8 have a prevalence of over 2%, and the remaining SCAs are thought to be rare (prevalence 450 CAG repeats. Immunoblott analysis demonstrated that ataxin-7 is widely expressed but that expression levels vary among tissues. Instability of expanded repeats is more pronounced in SCA7 than in other SCA subtypes and can cause substantial lowering of age at onset in successive generations termed 'anticipation' so that children may become diseased even before their parents develop symptoms. The strong anticipation in SCA7 and the rarity of contractions should have led to its extinction within a few generations. There is no specific drug therapy for this neurodegenerative disorder. Currently, therapy remains purely symptomatic. Cellular models and SCA7 transgenic mice have been generated which constitute valuable resources for studying the disease mechanism. Understanding the pathogenetic mechanisms of neurodegeneration in SCAs should lead to the identification of potential therapeutic targets and ultimately facilitate drug discovery. Here we summarize the clinical, pathological, and genetic aspects of SCA7, and review the current understanding of the pathogenesis of this disorder. Further, we also review the potential therapeutic strategies that are currently being explored in polyglutamine diseases.

A Case Report of X-linked Recessive Bulbospinal Muscular Atrophy (Kennedy`s Syndrome)

We had 58-year-old-man with chronic lower back pain, progressive whole extremities and facial muscle weakness, dysarthria and recurrent aspiration during swallowing, without any sensory disturbance. His two brothers had similar symptoms from their 6th decade. He had muscle atrophy on tongue, both hand lower leg muscles with some fasciculations. All tendon reflexes were absent without pathologic pyramidal reflex. Nerve conduction studies revealed low median, ulnar, and sural sensory nerve action potential amplitude. On EMG study, there were chronic denervation potentials on most of muscles of extremities. On DNA analysis, there were abnormal expansions of CAG repeats in the androgen receptor gene. We confirmed a X-linked recessive bulbospinal muscular atrophy (Kennedy's syndrome).

The association of CAG repeat length polymorphisms of androgen receptor gene and spermatogenesis impairment in several Indonesian men.

Spermatogenesis impairment is the main cause of infertility in men. Androgen is believed to play a critical role in regulating spermatogenesis. Androgen acts by binding to the androgen receptor (AR) which is a protein regulator of DNA transcription. Exon 1 of AR gene contains a CAG repeat length polymorphism and it is believed to interfere AR function. This study includes DNA isolation from peripheral blood and amplification of CAG repeat fragments by PCR method. CAG repeat lengths were determined by electrophoresis on 6% denaturing gel polyacrylamide. We found that the mean CAG repeat lengths were 24,3 ± 3,4 in oligozoospermic/azoospermic men and 22,7 ± 2,7 in normozoospermic men. The difference in CAG repeat length between the two groups was statistically significant (p = 0,031, t-test). Nevertheless, there was no correlation between CAG repeat lengths and sperms concentration (rs = -0,038; p = 0,775). This result suggest that the expansion of CAG repeat length was not the main cause of spermatogenesis impairment.

Tardive Dyskinesia and CAG Repeat Expansions / 신경정신의학

OBJECTIVES: Much interest has recently been focused on the possibility of the involvement of unstable DNA in the etiology of schizophrenia following several publications that reported increases in frequency of large CAG repeats in affected individuals. Tardive dyskinesia(TD), an involuntary movement disorder following pharmacological treatment of schizophrenia, shares a great deal of common clinical and biological features with Huntington's disease, a representative movement disorder with CAG repeat expansions. The authors studied for a possible CAG repeat expansions in patients with schizophrenia and TD. METHODS: TD was diagnosed by the Abnormal Involuntary Movement Scale. Using repeat expansion detection(RED), a method in which a thermostable ligase is used to detect repeat expansions directly from genomic DNA, subjects with schizophrenia with/without TD(n=79/n=75) and normal controls (n=72) were studied for the presence of the CAG repeat expansions were analyzed. RESULTS: No significant size differences were detected in the(CTG)17 ligation products between schizophrenic cases and controls using RED(X(2)=2.907, df=2, p=0.234). CONCLUSIONS: This finding does not support the hypothesis that CAG repeat expansions contributes to the susceptibility for schizophrenia and TD.

Preliminary study of relationship between the CAG repeat polymorphism of androgen receptor gene and benign prostatic hyperplasia in Xinjiang Uygur men / 中华泌尿外科杂志

0.05).But the association between (CAG)n repeats and prostate volume was significant (P

Spinocerebellar Ataxia Type 6 in Two Korean Families

BACKGROUND: Spinocerebellar ataxia 6 (SCA6) is an autosomal dominant spinocerebellar degeneration and caused by the expansion of the polymorphic CAG repeat in the human alpha 1A voltage-dependent calcium channel subunit gene. In this study, we report the clinical and molecular genetic characteristics of SCA6 in 2 Korean families. We further describe that SCA6 and Episodic ataxia type 2 are simultaneously developed in same family showing no intergenerational changes of CAG repeat numbers. METHODS: Seventeen members of one family and nine of the other received detailed neurological examination and history taking at least one occasion. After the screening test, molecular diagnostic test by using Zhuchenko's method were performed in 13 patients in one family and 3 in the other, respectively. RESULTS: Normal range of CAG repeat in 92 normal individuals was 8 to 17. In this study, the numbers of CAG repeat in one family was 26 and in another was 23. There were no intergenerational differences in the numbers of CAG repeat. Despite the same number of CAG repeat, the clinical anticipation were found. Only one showed episodic ataxia clinically. CONCLUSIONS: Comparing with other types of SCA, the SCA6 had several remarkable characteristics: 1) very small CAG expansions (21-27 repeats) lead to clinical symptoms and the repeat numbers are relatively stable, 2) clinical anticipation is observed despite the relatively stable repeat on intergenerational transmission. The finidngs that an EA2 and a SCA6 exist in a same family may be suggest that two disease are the same disorder with a high phenotypic variablity.

A Case of Huntington's Disease without Family History Who Has Diagnosed with CAG Repeat Expansion / 신경정신의학

We report a 48-year-old female with typical symptoms of Huntington's disease, including involuntary movement, cognitive dysfunction and psychiatric symptoms such as personality change, emotional instability, persecutory ideation and depression, but without family history. The diagnosis of HD was confirmed a repetitive DNA sequence(CAG) amplification on HD locus by PCR and pAGE in this case. The DNA analysis showed that she had an allele with 43 repeat units, in the size range seen in HD chromosomes. So we reported this case with literature review.

CAG repeat expansion in the SCA7 in Korean families presenting clinical features compatible with ADCA type II

BACKGROUND: Autosomal dominant cerebellar ataxia type II(ADCA type II) can be differentiated from other types of ADCA by visual disturbances due to pigmentary macular degeneration. Recent genetic studies repeatedly mapped the gene responsible for ADCA type II to chromosome 3p12-13(SCA7) in caucasian patients. However, in Asian patients CAG expansion at the SCA7 locus has not yet been reported. METHODS: We analyzed clinical data obtained from three Korean families in which 14 members presented clinical features compatible with ADCA type II. We also performed a genetic study for 17 members (7 affected and 10 asymptomatic) from two of the three families. RESULTS All seven affected patients had abnormally increased CAG repeat numbers (range : 38-59) in SCA7. One asymptomatic 23-year-old woman had 45 CAG repeats in the SCA7. Other 9 asymptomatic family members had 10 CAG repeats in the SCA7. CONCLUSION: We showed that as caucasian patients, Asian patients with ADCA type II also have abnormally increased CAG repeats at SCA7.

Diagnosis of Huntington's disease with Polymerase Chain Reaction

Huntington's disease is an autosomal dominant neurodegenerative disorder that usually begins in mid-life and is characterized by a progression of involuntary choreiform movements, personality change, and dementia. 4 specific unstable trinucleotide (CAG) repeat expansion in a gene on the short arm of chromosome 4 was recently identified as the pathogenic mutation for this disease. We have analysed the CAG expansion in peripheral leukocyte from a woman suspected with Huntington's disease and her family. A 40-year-old woman visited for the 6 years history of progressing intractable involuntary hyperkinetic movement and antagonistic personality. She showed bilateral caudate nucleus atrophy with mild enlargement of both frontal horn at brain MRI and showed the decrement of glucose metabolism in both basal ganglia at 18F-FDG PET scan. We also studied about the clinical manifestations of her family. Her younger brother also showed mild cognitive impairment and dysarthria. She and her relatives (n = 6) were tested for the existence of high risk allele of Huntington's disease by polymerase chain reaction method. The high risk allele (above 40 CAG repeat) in the 1715 gene was confirmed in 6 persons including the patient. The CAG repeat variance was 46 to 54. Only one person showed the normal range of CAG repeat.