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1.
Long repeat tracts at SCA8 in major psychosis 总被引:3,自引:0,他引:3
Vincent JB Yuan QP Schalling M Adolfsson R Azevedo MH Macedo A Bauer A DallaTorre C Medeiros HM Pato MT Pato CN Bowen T Guy CA Owen MJ O'Donovan MC Paterson AD Petronis A Kennedy JL 《American journal of medical genetics》2000,96(6):873-876
Expansion at a recently identified unstable trinucleotide repeat on chromosome 13q21 has been reported as the molecular cause for spinocerebellar ataxia type 8 (SCA8). The trinucleotide repeat, which consists of a [CTA]n repeat and adjacent [CTG]n repeat, was reported to have a pathogenic range of 107-127 CTG repeats (or 110-130 combined CTA and CTG repeats) in a large ataxia kindred. This repeat region was also cloned by our group from a bipolar affective disorder (BPAD) patient, who has approximately 600 combined repeats, and large alleles (>100 repeats) were reported to be present in 0.7% of controls and 1.5% of major psychosis patients (n = 710 and n = 1,120, respectively). We have followed up these findings by screening three new samples of BPAD and schizophrenia (SCZ) patients and controls, including 272 individuals from 14 BPAD families from Sweden, 130 individuals from 32 SCZ and BPAD families/trios from the Azores Islands, and 206 SCZ individuals from the United Kingdom and Ireland, and 219 matched controls. We found large repeat alleles above the SCA8 pathogenic range in individuals from 3 of 32 Azorean pedigrees and in 1 of 206 SCZ individuals from the United Kingdom, and repeat alleles within the SCA8 pathogenic range in 1 of 14 Swedish families. Although the rarity of major psychosis patients carrying the SCA8 expansion mutation would require a much larger sample size to reach statistical significance, these results support the previously reported observation of increased occurrence of large repeats at SCA8 in major psychosis. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:873-876, 2000. 相似文献
2.
Population genetics of trinucleotide repeat polymorphisms 总被引:2,自引:1,他引:1
Trinucleotide repeats at five disease loci (DM, DRPLA, HD, SBMAand SCA1) were surveyed in phenotypically normal individualsfrom three continental populations. This is the first analysisto examine the population dynamics of these five disease-relatedtrinucieotide repeats in the same individuals from worldwidepopulations. Roughly half of all alleles observed at each locusare shared between all continental groups. For three loci, diseaseprevalence in each population corresponds with the number ofalleles in the upper tail of the allele-size distribution. Theallele-size distributions of African, Asian and Caucasian groupsshow a high degree of variation, and gene diversity estimatesfor trinucieotide repeat loci exceed estimates derived fromdinucleotide or tetranucleotide repeats. Analyses that comparedinfinite alleles and stepwise mutation models suggest that normalvariation at trinucieotide loci is not generated by stepwisemutation alone. Trees constructed for subpopulations using trinucieotiderepeat loci show accurate continental clustering. Interpopu-lationgenetic distance estimates show remarkable similarity to distanceestimates produced from tetranucleotide repeats or nuclear restrictionsite polymorphisms. This finding is especially noteworthy inlight of the fact that trinucieotide repeat polymorphisms atthese loci can cause disease, while restriction site and tetranucleotidepolymorphisms appear to be selectively neutral. In contrast,genetic distance estimates from trinucieotide loci are poorlycorrelated with genetic distance estimates from mitochondrialsequence data. 相似文献
3.
Fourteen and counting: unraveling trinucleotide repeat diseases 总被引:8,自引:0,他引:8
4.
Increased trinucleotide repeat instability with advanced maternal age 总被引:15,自引:14,他引:1
Nucleotide repeat instability is associated with an increasing number of
cancers and neurological disorders. The mechanisms that govern repeat
instability in these biological disorders are not well understood. To
examine genetic aspects of repeat instability we have introduced an
expanded CAG trinucleotide repeat into transgenic mice. We have detected
intergenerational CAG repeat instability in transgenic mice only when the
transgene was maternally transmitted. These intergenerational instabilities
increased in frequency and magnitude as the transgenic mother aged.
Furthermore, triplet repeat variations were detected in unfertilized
oocytes and were comparable with those in the offspring. These data show
that maternal repeat instability in the transgenic mice occurs after
meiotic DNA replication and prior to oocyte fertilization. Thus, these
findings demonstrate that advanced maternal age is an important factor for
instability of nucleotide repeats in mammalian DNA.
相似文献
5.
Grierson AJ van Groenigen M Groot NP Lindblad K Hoovers JM Schalling M de Belleroche J Baas F 《European journal of human genetics : EJHG》1999,7(1):12-19
Expansions of trinucleotide CAG repeats have been demonstrated in at least eight neurodegenerative disorders, and suggested to occur in several others, including bipolar disorder and schizophrenia. Chromosome 18 loci have been implicated in bipolar disorder pedigrees by linkage analysis. To address this putative link between chromosome 18 CAG trinucleotide repeats and neuropsychiatric illness, we have screened a chromosome 18 cosmid library (LL18NCO2" AD") and identified 14 novel candidate loci. Characterisation of these loci involved repeat flank sequencing, estimation of polymorphism frequency and mapping using FISH as well as radiation hybrid panels. These mapped trinucleotide loci will be useful in the investigation of chromosome 18 in neurodegenerative or psychiatric conditions, and will serve to integrate physical and radiation hybrid maps of chromosome 18. 相似文献
6.
To provide the clinical diagnostics community with accurate protocols and measurements for the detection of genetic disorders, we have established a quantitative measurement program for trinucleotide repeats associated with human disease. In this study, we have focused on the triplet repeat associated with fragile X syndrome. Five cell lines obtained from the Coriell Cell Repository were analyzed after polymerase chain reaction (PCR) amplification and size separation. These cell lines were reported to contain CGG repeat elements (ranging from 29 to 110 repeats). Our initial measurements focused on measurement variability: (a) between slab-PAGE and capillary (CE) separation systems (b) interlane variability (slab-PAGE) (c) intergel variability, and (d) variability associated with amplification. Samples were run in triplicate for all measurements, and the analysis performed using Gene Scan analysis software. The repeat sizes were verified by DNA sequence analyzes. The standard deviations for interlane measurements in slab-gels ranged from 0.05 to 0.35. There was also little variation in size measurements performed on different gels and among PCR amplifications. The CGG repeat measurements performed by capillary electrophoresis were more precise, with standard deviations ranging from 0.02 to 0.29. The slab-PAGE and CE size measurements were in agreement except for the pre-mutation alleles, which yielded significantly smaller sizes by CE. 相似文献
7.
8.
The correlation of age of onset with CTG trinucleotide repeat amplification in myotonic dystrophy. 总被引:6,自引:0,他引:6
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A Hunter C Tsilfidis G Mettler P Jacob M Mahadevan L Surh R Korneluk 《Journal of medical genetics》1992,29(11):774-779
The gene for myotonic dystrophy (DM) has recently been isolated and amplification of an unstable CTG trinucleotide repeat, located within the DM gene, has been identified in virtually all patients studied to date. A high proportion of DM families who are studied show a progressively earlier age of onset with succeeding generations and, in the few pedigrees reported so far, an increasing degree of amplification of the CTG repeat has been noted to parallel this trend. It has been implicit in several of the original reports on the nature of the changes in the DM gene that knowledge of CTG amplification status at the DM locus of a person will provide useful information concerning prognosis. However, no studies of genotype-phenotype correlation have been reported and there are no specific data on which to base such counsel. In this paper we report the correlation between the degree of CTG amplification and age of onset in 109 DM gene carriers from 17 families. Included are parent-child and sib-sib comparisons which provide a framework in which to incorporate DNA diagnostic studies when counselling subjects and families at risk for DM. 相似文献
9.
Yuan QP Lindblad-Toh K Zander C Burgess C Durr A Schalling M 《International journal of molecular medicine》2001,8(4):427-431
Until today, nineteen trinucleotide repeat expansions larger than forty repeat copies have been found in the human genome. Of these, the CAG/CTG repeat is predominant motif with twelve loci identified, ten of which have been associated with the development of neurodegenerative diseases. We have developed a cloning approach which isolates disease genes containing trinucleotide repeat expansions. The method is based on size separation of genomic fragments, followed by subcloning and library hybridization with an oligonucleotide probe. Fractions and clones containing expanded repeats are identified by the repeat expansion detection (RED) method throughout the cloning procedure. Large family materials are not required and as little as 10 microg genomic DNA from a single individual is sufficient for this method. Using this strategy we have cloned two DNA fragments containing expanded repeats from two unrelated patients with a clinical diagnosis of cerebellar ataxia. Sequencing of the two fragments showed sequence identities with two disease genes, the Huntington gene and the ataxin 3 gene, respectively. The method should be adaptable to the cloning of any long repeat motif in any species. Furthermore the experimental steps can be performed in less than a month, making it very effective and time efficient to disease gene identification. 相似文献
10.
Trinucleotide repeat sequences are widely present in the human genome. The expansion of CAG repeats have been studied very extensively, and shown to be the causative mechanism of more than 40 neuromuscular and neurodegenerative diseases. In the present study, we performed a genome wide screening of CAG repeat expansions in non-neoplastic tissues of 212 breast cancer cases and 196 healthy population controls using the Repeat Expansion Detection (RED) method. Distribution of CAG repeat lengths in cases was not significantly different from controls. However, dramatically expanded CAG repeats were detected in 2.4% (n=5) of breast cancer cases where no repeats of similar size were detected in any of the healthy population controls. Although this trend shows only borderline significance (p=0.06), this finding suggests a potential involvement of CAG repeat expansion in breast cancer susceptibility. These repeats may potentially affect the function of cancer predisposition genes, with a similar mechanism as in neurodegenerative and neuromuscular disorders. 相似文献
11.
12.
Nenguke T Aladjem MI Gusella JF Wexler NS Arnheim N;Venezuela HD Project 《Human molecular genetics》2003,12(9):1021-1028
The positions of DNA replication initiation regions (IRs) at three human trinucleotide repeat (TNR) disease loci were examined in order to characterize the role played by IRs in explaining the known locus-specific variation in TNR instability levels. Using three different normal cell lines, candidate IRs were identified at the HD, SCA-7 and SBMA loci. At each locus the IR is less than 3.6 kb from the CAG/CTG repeat tract. Preliminary studies with a cell line homozygous for an HD disease mutation indicated no change in the position of the candidate IR in spite of the mutation. Comparison with experimental results from model systems suggests that a complex relationship may exist between instability and the proximity and/or orientation of the repeats with respect to an IR. 相似文献
13.
Segregation ratio distortion (SRD) with preferential transmission of expanded CAG alleles has been reported in Machado-Joseph disease (MJD/SCA3), spinocerebellar ataxia type I (SCA1), and dentatorubral-pallidoluysian atrophy (DRPLA). We have examined the transmission frequencies of alleles in normal heterozygotes at these disease loci in 377 pairs of twins and their parents and find no evidence for SRD. 相似文献
14.
V Biancalana F Serville J Pommier J Julien A Hanauer J L Mandel 《Human molecular genetics》1992,1(4):255-258
Increased length of a protein-coding CAG repeat within the androgen receptor gene appears to be the only type of mutation responsible for spino-bulbal muscular atrophy (SBMA or Kennedy disease). We have analysed a large 4-generation SBMA family and found that the mutant allele was unstable upon transmission from parent to child, with a documented variation from 46 to 53 repeats and a tendency to increase in size (7 increases and a single decrease in 17 events), which appeared stronger upon transmission from a male than from a female. Our results suggest also limited somatic instability of the abnormal allele, with observable variation of up to 2-3 repeats. This indicates that the behavior of the CAG repeat is similar to that observed for small premutations in the fragile X syndrome, or small abnormal alleles in myotonic dystrophy, two diseases which are caused by expansion of an unstable trinucleotide repeat. 相似文献
15.
Analysis of the trinucleotide repeat expansion in Italian families affected with Huntington disease 总被引:12,自引:5,他引:7
Novelletto Andrea; Persichetti Francesca; Sabbadin Guglielmo; Mandich Paola; Bellone Emilia; Ajmar Franco; Pergola Mariano; Senno Laura Del; E.MacDonald Marcy; F.Gusella James; Frontall Marina 《Human molecular genetics》1994,3(1):93-98
150 subjects affected with HD and 45 at high risk for the diseasewere typed for the CAG trinucleotide repeat at the 5end of IT15. In all of them we find expanded segments showingmarked instability upon transmission. Their length distributionmatches those previously reported and inversely correlates (0.686)with age at onset. Two at risk sibs from a large HD pedigreeshow expanded segments that overlap the normal distributionand can represent reductions from the HD to the normal range.A case of instability on a normal chromosome is also reported.Finally, an analysis of the CAG repeat as a function of threepolymorphic DNA markers at D4S127 and D4S95 loci shows no significantdifference in the average repeat length on HD chromosomes groupedaccording to the cosegregating allele of each marker or to thecorresponding haplotype. Despite the marked heterogeneity inrepeat length among HD families, haplotypes are not associatedwith different values around which the repeat length fluctuates. 相似文献
16.
17.
为在分子水平了解安徽人亨廷顿病(HD)的发病机制,为该病的基因诊断和遗传咨询提供科学依据.应用巢式PCR,变性聚丙烯酰胺凝胶电泳以及DNA测序等方法,对6例正常安徽人以及6例HD家系的研究结果表明中国人正常IT15基因(CAG)n重复序列的拷贝数为13-26,而所有被分析的HD患者都携带一个CAG序列高度重复的IT15基因,其(CAG)n的拷贝数为40-94;且CAG重复序列的拷贝数与发病年龄呈现一定的相关性. 相似文献
18.
Androgen receptor YAC transgenic mice carrying CAG 45 alleles show trinucleotide repeat instability 总被引:1,自引:15,他引:1
La Spada AR; Peterson KR; Meadows SA; McClain ME; Jeng G; Chmelar RS; Haugen HA; Chen K; Singer MJ; Moore D; Trask BJ; Fischbeck KH; Clegg CH; McKnight GS 《Human molecular genetics》1998,7(6):959-967
X-linked spinal and bulbar muscular atrophy (SBMA) is caused by a CAG
repeat expansion in the first exon of the androgen receptor (AR) gene.
Disease-associated alleles (37-66 CAGs) change in length when transmitted
from parents to offspring, with a significantly greater tendency to shift
size when inherited paternally. As transgenic mice carrying human AR cDNAs
with 45 and 66 CAG repeats do not display repeat instability, we attempted
to model trinucleotide repeat instability by generating transgenic mice
with yeast artificial chromosomes (YACs) carrying AR CAG repeat expansions
in their genomic context. Studies of independent lines of AR YAC transgenic
mice with CAG 45 alleles reveal intergenerational instability at an overall
rate of approximately 10%. We also find that the 45 CAG repeat tracts are
significantly more unstable with maternal transmission and as the
transmitting mother ages. Of all the CAG/CTG repeat transgenic mice
produced to date the AR YAC CAG 45 mice are unstable with the smallest
trinucleotide repeat mutations, suggesting that the length threshold for
repeat instability in the mouse may be lowered by including the appropriate
flanking human DNA sequences. By sequence-tagged site content analysis and
long range mapping we determined that one unstable transgenic line has
integrated an approximately 70 kb segment of the AR locus due to
fragmentation of the AR YAC. Identification of the cis - acting elements
that permit CAG tract instability and the trans -acting factors that
modulate repeat instability in the AR YAC CAG 45 mice may provide insights
into the molecular basis of trinucleotide repeat instability in humans.
相似文献
19.
Human MSH2 binds to trinucleotide repeat DNA structures associated with neurodegenerative diseases 总被引:5,自引:5,他引:5
The expansion of trinucleotide repeat sequences is associated with several
neurodegenerative diseases. The mechanism of this expansion is unknown but
may involve slipped-strand structures where adjacent rather than perfect
complementary sequences of a trinucleotide repeat become paired. Here, we
have studied the interaction of the human mismatch repair protein MSH2 with
slipped-strand structures formed from a triplet repeat sequence in order to
address the possible role of MSH2 in trinucleotide expansion. Genomic
clones of the myotonic dystrophy locus containing disease-relevant lengths
of (CTG)n x (CAG)n triplet repeats were examined. We have constructed two
types of slipped-strand structures by annealing complementary strands of
DNA containing: (i) equal numbers of trinucleotide repeats (homoduplex
slipped structures or S-DNA) or (ii) different numbers of repeats
(heteroduplex slipped intermediates or SI-DNA). SI-DNAs having an excess of
either CTG or CAG repeats were structurally distinct and could be separated
electrophoretically and studied individually. Using a band-shift assay, the
MSH2 was shown to bind to both S-DNA and SI-DNA in a structure- specific
manner. The affinity of MSH2 increased with the length of the repeat
sequence. Furthermore, MSH2 bound preferentially to looped-out CAG repeat
sequences, implicating a strand asymmetry in MSH2 recognition. Our results
are consistent with the idea that MSH2 may participate in trinucleotide
repeat expansion via its role in repair and/or recombination.
相似文献
20.
T. C. Brown J. C. Tarleton R. C. P. Go J. W. Longshore M. Descartes 《American journal of medical genetics. Part A》1997,73(4):447-455
The fragile sites FRAXA and FRAXE, located ∼600 kb apart on Xq27.3 and Xq28, respectively, are due to a CGG trinucleotide repeat expansion. Although the expansion mechanism for these and other trinucleotide repeat disorders remains unknown, the similarities between the FRAXA and FRAXE regions suggest a possible association between the 2 sites. DNA from 953 individuals was analyzed to determine the distribution of FRAXE repeat sizes in this population and to ascertain potential association between FRAXA and FRAXE repeat sizes. Thirty-four FMR2 alleles ranging from 3–42 repeats were identified. No FRAXE expansions were found in this population, supporting previous findings that FRAXE expansions are rare. However, in the fragile X syndrome affected group, a FMR2 delection, 2 cases of FRAXE repeat instability and a FRAXE mosaic male were identified. Also, a previously identified, rare FMR2 polymorphism was observed. Statistical analyis showed no correlation between normal FRAXA and FRAXE repeat sizes studied, although there was a significant size difference in larger FMR2 alleles that segregated with expanded FMR1 alleles. These findings support the idea of an association between repeat expansion in the FMR1 gene and instability or deletions in the FMR2 gene. Am. J. Med. Genet. 73:447–455, 1997. © 1997 Wiley-Liss, Inc. 相似文献