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1.
Sequence analysis of the CCG polymorphic region adjacent to the CAG triplet repeat of the HD gene in normal and HD chromosomes. 总被引:1,自引:0,他引:1 下载免费PDF全文
C Pêcheux J F Mouret A Dürr Y Agid J Feingold A Brice C Dodé J C Kaplan 《Journal of medical genetics》1995,32(5):399-400
The CAG expansion responsible for Huntington's disease (HD) is followed by an adjacent polymorphic CCG repeat region which may interfere with a PCR based diagnosis. We have sequenced this region in 52 unrelated HD patients, from both normal and HD chromosomes. Fifty percent of the normal alleles were (CCG)7(CCT)2, 48% (CCG)10(CCT)2, and 2% (CCG)7(CCT)3. In contrast (CCG)7(CCT)2 was found in 85% of the HD alleles which represents significant linkage disequilibrium with the HD mutation. 相似文献
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David C. Rubinsztein Jayne Leggo Sandy Goodburn David E. Barton Malcolm A. Ferguson-Smith 《American journal of medical genetics. Part A》1995,60(2):109-110
The clinical features of Parkinson's disease, particularly rigidity and bradykinesia and occasionally tremor, are seen in juvenile-onset Huntington's disease. Therefore, the CAG and CCG repeats in the Huntington's disease gene were investigated in 45 Parkinson's disease patients and compared to 40 control individuals. All of the Parkinson's disease chromosomes fell within the normal size ranges. In addition, the distributions of the two repeats in the Parkinson's disease patients did not differ significantly from those of the control population. Therefore, abnormalities of these trinucleotide repeats in the Huntington's disease gene are not likely to contribute to the pathogenesis of Parkinson's disease. © 1995 Wiley-Liss, Inc. 相似文献
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Study of the Huntington''s disease (HD) gene CAG repeats in schizophrenic patients shows overlap of the normal and HD affected ranges but absence of correlation with schizophrenia. 总被引:2,自引:0,他引:2 下载免费PDF全文
D C Rubinsztein J Leggo S Goodburn T J Crow R Lofthouse L E DeLisi D E Barton M A Ferguson-Smith 《Journal of medical genetics》1994,31(9):690-693
The CAG repeats in the Huntington's disease gene were investigated in chromosomes from 71 unrelated schizophrenic persons and 18 patients with schizoaffective disorder in order to determine if any of these patients had abnormal expansions. All of the probands had repeat sizes in the normal range (< 35 repeats) and there was no significant difference between the allele distributions of these patients and the normal controls. The families of two patients with 32 repeats and one patient with 34 repeats were investigated further and showed no uniform segregation of the disease with the large repeat alleles. The proband with 34 repeats inherited a chromosome that originally had 36 repeats in her father. The presence of 36 CAG repeats in members of her family and in HD patients suggests that there is an overlap between the normal and Huntington's disease CAG repeat size ranges. The more recently described CCG polymorphism in this gene was also examined in the schizophrenic and schizoaffective persons. All patients had alleles in the normal range. 相似文献
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Limprasert P; Nouri N; Heyman RA; Nopparatana C; Kamonsilp M; Deininger PL; Keats BJ 《Human molecular genetics》1996,5(2):207-213
Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative
disorder associated with an unstable and expanded CAG repeat. We analyzed
this locus from various sources including MJD families, Acadian, African
American, Caucasian, Greenland Inuit and Thai populations. The range of the
CAG repeat size was 14-40 in the normal alleles while the MJD alleles
contained 73-78 repeats in our studies. We found 25 different alleles on
normal chromosomes with a heterozygosity of 0.86 in combined populations.
The most common alleles were 23 (22.9%) and 14 (25.5%) repeats. We also
examined 16 chimpanzees and various Old World monkeys: a pigtail macaque, a
mangabey and 12 rhesus macaques. The DNA sequences surrounding the CAG
repeat did not vary among species. The range of the number of the CAG
repeats is 13-14 in macaques, 16 in mangabey and 14-20 in chimpanzees.
Variant CAA or AAG triplets in the CAG repeat tracts were found in all 268
human, 28 monkey and 32 chimpanzee chromosomes. As reported in a previous
study [Kawaguchi et al. (1994) Nature Genet. 8, 221-228] the common variant
positions were the third (CAA), fourth (AAG) and sixth (CAA) positions.
However, we found three human chromosomes containing CAG at the sixth
position and the mangabey had AAG at the ninth position. In addition, we
found CAG at the fourth position and AAG at the sixth position in all
macaque chromosomes. The nucleotide following the CAG repeat tract was
usually G in all species studied. However, we sometimes found C at this
position in human and chimpanzee chromosomes. Interestingly, this variant C
was found in all expanded chromosomes and in 54.5% of chromosomes with
27-40 CAG repeats but it was not found in any chromosomes with less than 20
CAG repeats. We hypothesize that the variant C may be associated with CAG
repeat instability.
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6.
Takiyama Y; Sakoe K; Amaike M; Soutome M; Ogawa T; Nakano I; Nishizawa M 《Human molecular genetics》1999,8(3):453-457
Dentatorubral-pallidoluysian atrophy (DRPLA) is known to show the most
prominent genetic anticipation among CAG repeat diseases. To investigate
the mechanism underlying the meiotic instability of expanded CAG repeats in
the gene for DRPLA, we determined the CAG repeat sizes of 427 single sperm
from two individuals with DRPLA. The mean variance of the change in the CAG
repeat size in sperm from the DRPLA patients (288.0) was larger than any
variances of the CAG repeat size in sperm from patients with Machado-Joseph
disease (38. 5), Huntington's disease (69.0) and spinal and bulbar muscular
atrophy (16.3), which is consistent with the clinical observation that the
genetic anticipation on the paternal transmission of DRPLA is the most
prominent among CAG repeat diseases. The variance of the change in CAG
repeat size was significantly different between the two DRPLA patients
(F-test, P < 0.0001). However, the segregation ratio of single sperm
with an expanded allele to ones with a normal allele is not statistically
different ( P = 0.161) from the expected 1:1 segregation ratio, and thus
segregation distortion of expanded alleles in meiosis in male patients with
DRPLA was not demonstrated.
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7.
中国男性雄激素受体基因(CAG)n重复多态性的初步研究 总被引:16,自引:0,他引:16
目的 研究正常中国男性雄激素受体(androgen receptor,AR)基因(CAG)n重复序列的多态性。方法 应用DNA测序基础上的[α-^32P]dCTP掺入不对称PCR-变性聚丙烯酰胺凝胶电泳(Polyacrylamide gel electrophoresis,PAGE)方法,对107名正常男性AR基因的(CAG)n重复数进行测定。结果 AR基因(CAG)n序列在正常男性人群中呈现重复多态性,其重复范围为11-29,集中于20-24,以22最多。结论 AR基因(CAG)n序列在正常男性人群中呈现重复多态性,为今后进一步研究其病理学及遗传学意义打下基础。 相似文献
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Analysis of CAG trinucleotide repeats from mouse cDNA sequences 总被引:1,自引:0,他引:1
A number of human single gene disorders are now known to result from abnormal expansion of trinucleotide repeats. Spinal muscular bulbar atrophy, myotonic dystrophy, Huntington's Disease, spinocerebellar ataxia and dentatorubral-pallidoluysian atrophy are all caused by expansions of CAG repeats. Abnormal expansion of trinucleotide repeats has only so far been described in humans, and no mouse models exist for these diseases. In order to investigate trinucleotide repeat stability in mice, the Genbank and EMBL nucleotide databases were screened to find genes containing CAG repeats. Of the sequences selected, 32 were from mouse, and in 12 of these the repeat was in transcribed sequence and contained at least seven perfect repeats. These repeats were then analysed by PCR to evaluate the degree of variability of repeat length in the various genes. Two of the genes containing variable length CAG repeats, seven in absentia homologue 1b (Sinh1b), and choline acetyl transferase (Chat), which had not previously been mapped in the mouse genome, were mapped by linkage analysis in an interspecific backcross. Sinh1b maps very distally on the X chromosome, and Chat maps to chromosome 14. 相似文献
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Patients with Huntington's disease (HD) carrying CAG repeats beyond 60 are less frequently seen and clinical features of them have been rarely reported. We identified four unrelated patients carrying CAG repeats beyond 60 (84.0 ± 13.76, ranging from 74 to 104) from 119 Chinese HD patients via direct sequencing. These four were all early onset with a mean age at presenting symptom of 9.8 ± 1.71 years. Paternal transmission was found in three of them and the fourth was apparently sporadic. In addition, they had atypical onset symptoms including epilepsy, intellectual decline, tics and walking instability, which might lead the clinicians to make the wrong diagnosis in the early stage of disease. Our work explores clinical features of Chinese HD patients with an expanded CAG repeat over 60 and may help the clinicians make a correct diagnosis in the early stage of disease. 相似文献
12.
东北地区正常汉族人群 SCA1及 SCA3/MJD基因内CAG重复变异研究 总被引:3,自引:1,他引:3
目的 对东北地区 110名汉族正常人 SCA1及 SCA3/ MJD基因 (CAG) n拷贝进行检测 ,探讨其正常变异范围 ,并对临床诊断为遗传型脊髓小脑共济失调的 8个家系的 2 5例患者和 6个散发病例进行基因分型评价和症状前及产前诊断。方法 应用荧光 - PCR方法测定不同基因型片段长度 ,并进行 DNA序列分析。结果 SCA3/ MJD基因 (CAG) n正常变异范围为 14~ 38个拷贝 ,集中于 14个拷贝 ,其等位基因频率为 39.5 5 % ,杂合频率为 78.18% ,共 13种等位基因。检出一个家系先证者携带有 (CAG) 6 8的 SCA3/ MJD基因 ,并对该家系成员进行了症状前诊断 ,没有发现 (CAG) n拷贝异常突变 ;SCA1基因内 (CAG) n正常变异范围 2 0~ 39拷贝 ,集中于 2 6及 2 7次 ,等位基因频率分别为 34.0 9%和 2 0 .91% ,杂合频率为 84 .5 5 % ,共 13种等位基因 ;散发病例未检出 CAG扩展性突变。结论 SCA1及 SCA3/ MJD基因中 (CAG) n正常变异范围存在地区和种族差异 ,SCAs基因分型是该病症状前及产前诊断的首选策略。 相似文献
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CGG/CCG repeats exhibit orientation-dependent instability and orientation-independent fragility in Saccharomyces cerevisiae 总被引:2,自引:0,他引:2
An expansion to >200 CGG/CCG repeats (hereafter called CGG)in the 5' region of the FMR1 gene causes fragile X syndrome,and this locus becomes a folate-sensitive fragile site. We usedSaccharomyces cerevisiae as a model system to study the stabilityand fragility of CGG repeats. Tracts of (CGG)81 and (CGG)160were integrated onto a yeast chromosome in both orientationsrelative to the nearest replication origin. Tracts of this lengthare pre-mutation alleles in humans, with a high probabilityof expansion in future generations. The CGG tracts in yeastcolonies showed a length-dependent instability with longer tractsbeing more prone to contraction than shorter tracts. In addition,there was an orientation bias for tract stability with tractshaving fewer contractions when the CCG strand was the templatefor lagging strand synthesis. Expansions of the CGG tracts alsooccurred in an orientation-dependent manner, although at a lowerfrequency than contractions. To determine whether CGG tractsare fragile sites in yeast, the CGG tracts were flanked by directrepeats, and the rate of recombination between the repeats determined.Strains carrying the (CGG)160 tract in either orientation hada large increase in their rate of recombination compared witha no-tract control strain. Because this increase was dependenton genes involved in double-strand break repair, recombinationwas likely to be initiated by CGG tract-induced breakage betweenthe direct repeats. The observation of orientation-dependentinstability and orientation-independent fragility suggests thatat least some aspects of their underlying mechanisms are different.
+ Present address: Department of Biology, Tufts University, Medford,MA 02155, USA
§ To whom correspondence should be addressed. Tel: +1 609 2586770; Fax: +1 609 258 1701; Email: vzakian@princeton.edu 相似文献
16.
Jin DK Hwang HZ Oh MR Kim JS Lee M Kim S Lim SW Seo MY Kim JH Kim DK 《Journal of affective disorders》2001,66(1):19-24
BACKGROUND: Trinucleotide repetition combined with variable penetrance of expression could be responsible for the complex transmission pattern observed in bipolar affective disorder (BPAD). The purpose of this study was to investigate the association of excess longer allele of KCNN3 and CTG18.1 in the patients with BPAD. METHODS: CAG/CTG repeat distribution in KCNN3, CTG 18.1 and ERDA1 was examined and the copy number of ligation product in repeat expansion detection (RED) was measured in Korean bipolar patients in comparison to ethnically matched healthy controls. RESULTS: No significant difference was found in the allele distribution of those repeats between bipolar patients and controls. Ligation product size in RED was not increased in bipolar patients. However, the copy number of ligation product in RED was highly correlated with CAG/CTG copies of ERDA1 (P=0.0001), partly with CTG 18.1 (P=0.04), but not with KCNN3. CONCLUSIONS: A longer CAG repeat alleles of KCNN3 or CTG 18.1 may not be a risk factor for BPAD in Korean population and the copy number of ligation product in RED in the patients with BPAD is influenced by the longer allele of CAG/CTG of ERDA1 or CTG 18.1. 相似文献
17.
We investigated the hypothesis that the trinucleotide repeat CAG is disproportionately located in exons in genomic DNA by analyzing unbiased genomic sequences with the Gene Recognition and Analysis Internet Link program ( http//avalon.epm.ornl.gov/ ). Forty percent of CAG/CTG repeats were predicted to lie within exons. This is significantly greater than would be expected by chance, and is also greater than we have observed for ATT/AAT repeats. Therefore, our data support the hypothesis. Furthermore, the data support the utility of a recently reported CAG/CTG PCR genomic screening set for identifying pathogenic expanded CAG/CTG repeats. Am. J. Med. Genet. 74:62–64, 1997. © 1997 Wiley-Liss, Inc. 相似文献
18.
Yanping Tang Ying Wang Ping Yang Yuan Liu Bo Wang Robert Podolsky Richard McIndoe Cong-Yi Wang 《American journal of medical genetics. Part B, Neuropsychiatric genetics》2006,(3):242-244
The prevalence of juvenile-onset Huntington's disease (HD) is about ten times lower than adult HD. Here we report a Chinese HD family showing both intergeneration CAG expansion and contraction. The expansion resulted from a paternal transmission which leads to juvenile-onset HD for a 17-year-old Chinese boy (III-5). More interestingly, a contraction was noticed in a maternal transmission (III-3), which changed the CAG repeat from an expanded, disease-causing allele (48 repeats) to a normal or intermediate allele (34 repeats). Of note, the contraction resulted in a deletion of 14 CAG repeats, which is much larger than previously reported contractions. Our results are consistent with previous observations in Western Caucasians that juvenile-onset HD is more likely inherited through the male germline. 相似文献
19.
目的 研究雄激素受体(androgen receptor,AR)基因(CAG)n、(GGN)n重复序列多态性在宁夏回、汉族群体中的分布特征.方法 用ABI 3730XL测序仪测定AR基因的(CAG)n及(GGN)n重复数目并对结果进行分析.结果 CAG等位基因在宁夏回、汉族群体中的分布差异无统计学意义(P>0.05).GGN等位基因在两个群体中的分布差异有统计学意义(P<0.01),汉族女性GGN重复数为23的等位基因频率(48.4%)显著低于回族女性(64.7%,P=0.01).结论 AR基因GGN等位基因在宁夏回、汉族群体中的分布差异有统计学意义(P<0.01). 相似文献
20.
Expansions of CAG.CTG repeats in immortalized human astrocytes 总被引:1,自引:0,他引:1
Expansions of trinucleotide repeats (TNRs) are the genetic cause for a number of neurodegenerative disorders. In some of these diseases, ongoing somatic expansions in the brain are thought to contribute to disease progression. Expansions can occur in both neurons and supporting glial cells, but little is known about molecular mechanisms of expansion in these cells, particularly glia. To help address this issue, a cultured human astrocyte cell line called SVG-A was tested for expansions of CAG*CTG repeats present on a shuttle vector. A quantitative genetic selection showed that +4 to +15 repeat expansions occur readily for starting alleles of 25 repeats, thereby spanning the important boundary between short stable repeats and longer more unstable CAG*CTG tracts. These expansions in glial cell culture, as in humans, were sequence and length-dependent, and were inhibited by the presence of a sequence interruption within the triplet repeat tract. These findings suggest that the mutations seen in cell culture reflect at least some of the in vivo expansions seen in glia. Mechanistically, it was found that the direction of DNA replication through the TNR influenced the frequency of expansions, suggesting that either replication or a replication-associated process, such as DNA repair, contributes to CAG*CTG tract instability in SVG-A cells. This finding is consistent with the idea that replication-based mechanisms can be a source of TNR expansions in astrocytes, which, unlike neurons, retain proliferative capacity throughout life. 相似文献