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1.
Takiyama Y; Sakoe K; Soutome M; Namekawa M; Ogawa T; Nakano I; Igarashi S; Oyake M; Tanaka H; Tsuji S; Nishizawa M 《Human molecular genetics》1997,6(7):1063-1068
To investigate the mechanism of the meiotic instability of expanded CAG
repeats in the gene for Machado-Joseph disease (MJD1), we analyzed the CAG
repeat sizes of 1036 single sperm from six individuals with Machado- Joseph
disease (MJD). The segregation ratio between single sperm with an expanded
allele and those with a normal allele is significantly different (P
<0.0001) from the expected 1:1 segregation ratio, which demonstrates
segregation distortion of expanded alleles in male meiosis. In single sperm
from individuals with the [expanded (CAG)n- CGG]/[normal (CAG)n-GGG]
genotype, significantly greater instability of the CAG repeat was observed
compared with single sperm from individuals with the [expanded
(CAG)n-CGG]/[normal (CAG)n-CGG] genotype (F-test, P <0.001). These
findings in single sperm confirm non-Mendelian transmission of the MJD1
gene and the effect of the intragenic CGG/GGG polymorphism on the
intergenerational instability of the CAG repeats in the MJD1 gene, which
have been observed in clinical and genetic studies. Our results indicate
similarities and dissimilarities between MJD and Huntington's disease or
myotonic dystrophy in terms of the inter-allelic interaction, segregation
distortions and size distribution of trinucleotide repeats in mutant
alleles. Further study is required to determine whether there is a common
mechanism underlying the instability of the triplet repeats in 'triplet
repeat diseases'.
相似文献
2.
Maciel P Gaspar C Guimarães L Goto J Lopes-Cendes I Hayes S Arvidsson K Dias A Sequeiros J Sousa A Rouleau GA 《European journal of human genetics : EJHG》1999,7(2):147-156
Intergenerational instability is one of the most important features of the disease-associated trinucleotide expansions, leading to variation in size of the repeat among and within families, which manifests as variable age at onset and severity, and is probably the basis for the occurrence of anticipation. Several factors are known to affect the degree of instability, namely the type of repeated sequence, its initial size, the presence or absence of interruptions in the repetitive tract and the gender of the transmitting parent. A recent study demonstrated the effect of an intragenic polymorphism (C987GG/G987GG) in the Machado-Joseph disease causative gene, immediately downstream of the CAG repeat, on the intergenerational instability of the expanded repeat. Surprisingly, there was an effect not only of the specific allele in cis to the disease chromosome, but also of the allele on the normal chromosome, suggesting the existence of an interaction between the normal and expanded alleles that affects the fidelity of replication of the (CAG)n tract. This effect could be a direct effect of the polymorphism studied or, alternatively, this polymorphism could be in disequilibrium with some other flanking sequence which affects the instability of the repetitive (CAG)n tract. In order to confirm the previous results in a different population and to distinguish between a direct and indirect effect of the CGG/GGG polymorphism, we typed 70 parent-progeny pairs for which the variation in the (CAG)n length in the MJD1 gene was known, for three intragenic polymorphisms: C987GG/G987GG and two additional, newly described ones, TAA1118/TAC1118 and A669TG/G669TG. We also typed a control population of 125 individuals for the A669TG/G669TG, C987GG/G987GG and TAA1118/TAC1118 polymorphisms, in an attempt to identify any association between haplotype and (CAG)n length in normal chromosomes, suggestive of an instability-predisposing effect of the repeat-flanking sequences, which could have led to the origin of the MJD mutation in the human population. We confirmed the effect of the C987GG/G987GG polymorphism on intergenerational instability when present in trans. Our results suggest that this effect is restricted to a small region of the gene, immediately downstream of the CAG repeat, which includes this particular nucleotide substitution and the stop codon of the MJD1 cDNA, and is not a more widespread chromosomal effect. The lack of a significant association of any specific intragenic haplotype with larger CAG repeats in normal chromosomes, together with the absence of an effect of the intragenic haplotype in cis on the intergenerational instability of the expanded (CAG)n in MJD families does not indicate the existence of an instability-predisposing haplotype. 相似文献
3.
Factors associated with ATXN2 CAG/CAA repeat intergenerational instability in Spinocerebellar ataxia type 2
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L.E. Almaguer‐Mederos J.M.L. Mesa Y. González‐Zaldívar D. Almaguer‐Gotay D. Cuello‐Almarales R. Aguilera‐Rodríguez N.S. Falcón S. Gispert G. Auburger L. Velázquez‐Pérez 《Clinical genetics》2018,94(3-4):346-350
Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disorder caused by the unstable expansion of a cytosine‐adenine‐guanine (CAG)/cytosine‐adenine‐adenine (CAA) repeat in the ATXN2 gene, which normally encodes 22 glutamines (Q22). A large study was conducted to characterize the CAG/CAA repeat intergenerational instability in SCA2 families. Large normal alleles (Q24‐31) were significantly more unstable upon maternal transmissions. In contrast, expanded alleles (Q32‐750) were significantly more unstable during paternal transmissions, in correlation with repeat length. Significant correlations were found between the instability and the age at conception in paternal transmissions. In conclusion, intergenerational instability at ATXN2 locus is influenced by the sex, repeat length and age at conception of the transmitting parent. These results have profound implications for genetic counseling services. 相似文献
4.
Repeat instability and motor incoordination in mice with a targeted expanded CAG repeat in the Sca1 locus 总被引:3,自引:0,他引:3
To elucidate the pathophysiology of spinocerebellar ataxia type 1 (SCA1) and to evaluate repeat length instability in the context of the mouse Sca1 gene, we generated knock-in mice by inserting an expanded tract of 78 CAG repeats into the mouse Sca1 locus. Mice heterozygous for the CAG expansion show intergenerational repeat instability (+2 to -6) at a much higher frequency in maternal transmission than in paternal transmission. The majority of changes transmitted through the female germline were small contractions, as in humans, whereas small expansions occurred more frequently in paternal transmission. The frequency of intergenerational changes was age dependent for both paternal and maternal transmissions. Mice homozygous for mutant ataxin-1 on a C57BL/6J-129/SvEv mixed background performed significantly less well on the rotating rod than did wild-type littermates at 9 months of age, although they were not ataxic by cage behavior. Histological examination of brain tissue from mutant mice up to 18 months of age revealed none of the neuropathological changes observed in other transgenic models overexpressing expanded polyglutamine tracts. These data suggest that, even with 78 glutamines, prolonged exposure to mutant ataxin-1 at endogenous levels is necessary to produce a neurological phenotype reminiscent of human SCA1. Pathogenesis is thus a function of polyglutamine length, protein levels and duration of neuronal exposure to the mutant protein. 相似文献
5.
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.
相似文献
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.
相似文献
7.
Wheeler VC Persichetti F McNeil SM Mysore JS Mysore SS MacDonald ME Myers RH Gusella JF Wexler NS;US-Venezuela Collaborative Research Group 《Journal of medical genetics》2007,44(11):695-701
Background
The Huntington disease (HD) CAG repeat exhibits dramatic instability when transmitted to subsequent generations. The instability of the HD disease allele in male intergenerational transmissions is reflected in the variability of the CAG repeat in DNA from the sperm of male carriers of the HD gene.Results
In this study, we used a collection of 112 sperm DNAs from male HD gene‐positive members of a large Venezuelan cohort to investigate the factors associated with repeat instability. We confirm previous observations that CAG repeat length is the strongest predictor of repeat‐length variability in sperm, but we did not find any correlation between CAG repeat instability and either age at the time of sperm donation or affectedness status. We also investigated transmission instability for 184 father–offspring and 311 mother–offspring pairs in this Venezuelan pedigree. Repeat‐length changes were dependent upon the sex of the transmitting parent and parental CAG repeat length but not parental age or birth order. Unexpectedly, in maternal transmissions, repeat‐length changes were also dependent upon the sex of the offspring, with a tendency for expansion in male offspring and contraction in female offspring.Conclusion
Significant sibling–sibling correlation for repeat instability suggests that genetic factors play a role in intergenerational CAG repeat instability. 相似文献8.
Costa MC Magalhães P Guimarães L Maciel P Sequeiros J Sousa A 《Journal of human genetics》2006,51(3):189-195
Huntington disease (HD) is caused by an expansion of a CAG repeat. This repeat is a dynamic mutation that tends to undergo intergenerational instability. We report the analysis of the CAG repeat in a large population sample (2,000 chromosomes) covering all regions of Portugal, and a haplotype study of (CAG)n and (CCG)n repeats in 140 HD Portuguese families. Intermediate class 2 alleles represented 3.0% of the population; and two expanded alleles (36 and 40 repeats, 0.11%) were found. There was no evidence for geographical clustering of the intermediate or expanded alleles. The Portuguese families showed three different HD founder haplotypes associated with 7-, 9- or 10-CCG repeats, suggesting the possibility of different origins for the HD mutation among this population. The haplotype carrying the 7-CCG repeat was the most frequent, both in normal and in expanded alleles. In general, we propose that three mechanisms, occurring at different times, may lead to the evolution from normal CAGs to full expansion: first, a mutation bias towards larger alleles; then, a stepwise process that could explain the CAG distributions observed in the more recent haplotypes; and, finally, a pool of intermediate (class 2) alleles more prone to give rise to expanded HD alleles. 相似文献
9.
Graldine Cancel Isabelle Gourfinkel-An Giovanni Stevanin Olivier Didierjean Nacer Abbas Etienne Hirsch Yves Agid Alexis Brice 《Human mutation》1998,11(1):23-27
An expanded and unstable CAG repeat in the coding region of the MJD1 gene is the mutation responsible for spinocerebellar ataxia 3/Machado-Joseph disease. In order to determine whether there was a higher degree of instability in affected regions, the size of the expanded CAG repeat was analyzed in different regions of the central nervous system, in two unrelated SCA3/MJD patients. The degree of somatic mosaicism was quantified and compared to that in a SCA1 patient. Instability of the expanded CAG repeat was observed in peripheral tissues as well as in CNS of the three patients, but there was no correlation between the degree of mosaicism and the selective vulnerability of CNS structures. As in the other diseases caused by expanded CAG repeats, a lower degree of mosaicism was found in the cerebellar cortex of both SCA1 and SCA3/MJD patients, probably reflecting specific properties of this structure. In SCA3/MJD, the degree of mosaicism seemed to correlate with age at death rather than with the size of the expanded CAG repeat. Finally, somatic instability was more pronounced in SCA1 than in SCA3/MJD patients. Hum Mutat 11:23–27, 1998. © 1998 Wiley-Liss, Inc. 相似文献
10.
CAG repeat instability at SCA2 locus: anchoring CAA interruptions and linked single nucleotide polymorphisms. 总被引:4,自引:0,他引:4
S Choudhry M Mukerji A K Srivastava S Jain S K Brahmachari 《Human molecular genetics》2001,10(21):2437-2446
Spinocerebellar ataxia 2 (SCA2) is an autosomal dominant neurodegenerative disorder that results from the expansion of a cryptic CAG repeat within the exon 1 of the SCA2 gene. The CAG repeat in normal individuals varies in length from 14 to 31 repeats and is frequently interrupted by one or more CAA triplets, whereas the expanded alleles contain a pure uninterrupted stretch of 34 to 59 CAG repeats. We have previously reported the presence of a limited pool of 'ancestral' or 'at risk' haplotypes for the expanded SCA2 alleles in the Indian population. We now report the identification of two novel single nucleotide polymorphisms (SNPs) in exon 1 of the SCA2 gene and their characterization in 215 normal and 64 expanded chromosomes. The two biallelic SNPs distinguished two haplotypes, GT and CC, each of which formed a predominant haplotype associated with normal and expanded SCA2 alleles. All the expanded alleles segregated with CC haplotype, which otherwise was associated with only 29.3% of the normal chromosomes. CAA interspersion analysis revealed that majority of the normal alleles with CC haplotype were either pure or lacked the most proximal 5' CAA interruption. The repeat length variation at SCA2 locus also appeared to be polar with changes occurring mostly at the 5' end of the repeat. Our results demonstrate that CAA interruptions play an important role in conferring stability to SCA2 repeat and their absence predisposes alleles towards instability and pathological expansion. Our study also provides new haplotypes associated with SCA2 that should prove useful in further understanding the mutational history and mechanism of repeat instability at the SCA2 locus. 相似文献
11.
Yoshihiro Suzuki Hidenao Sasaki Akemi Wakisaka Akio Takada Takashi Yoshiki Kiyoshi Iwabuchi Kunio Tashiro Toshiyuki Fukazawa Takeshi Hamada 《Journal of human genetics》1995,40(1):131-143
Summary SCA1 is caused by expansion of an unstable CAG triplet repeat in a novel gene located on the short arm of chromosome 6. In 126 Japanese individuals from 12 pedigrees with SCA1, studies were done to determine if they carried this mutant gene. All the affected and presymptomatic individuals, determined by haplotype segregation analyses, carried an abnormally expanded allele with the range of 39–63 repeat units. This repeat size inversely correlated with the age at onset. However, contrary to reported results, size of the repeat did not correlate with gender of the transmitting parent. Therefore, the CAG triplet repeat instability on paternal transmission is not likely to be fundamental to SCA1. 相似文献
12.
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
13.
Lloret A Dragileva E Teed A Espinola J Fossale E Gillis T Lopez E Myers RH MacDonald ME Wheeler VC 《Human molecular genetics》2006,15(12):2015-2024
Genetically precise models of Huntington's disease (HD), Hdh CAG knock-in mice, are powerful systems in which phenotypes associated with expanded HD CAG repeats are studied. To dissect the genetic pathways that underlie such phenotypes, we have generated Hdh(Q111) knock-in mouse lines that are congenic for C57BL/6, FVB/N and 129Sv inbred genetic backgrounds and investigated four Hdh(Q111) phenotypes in these three genetic backgrounds: the intergenerational instability of the HD CAG repeat and the striatal-specific somatic HD CAG repeat expansion, nuclear mutant huntingtin accumulation and intranuclear inclusion formation. Our results reveal increased intergenerational and somatic instability of the HD CAG repeat in C57BL/6 and FVB/N backgrounds compared with the 129Sv background. The accumulation of nuclear mutant huntingtin and the formation of intranuclear inclusions were fastest in the C57BL/6 background, slowest in the 129Sv background and intermediate in the FVB/N background. Inbred strain-specific differences were independent of constitutive HD CAG repeat size and did not correlate with Hdh mRNA levels. These data provide evidence for genetic modifiers of both intergenerational HD CAG repeat instability and striatal-specific phenotypes. Different relative contributions of C57BL/6 and 129Sv genetic backgrounds to the onset of nuclear mutant huntingtin and somatic HD CAG repeat expansion predict that the initiation of each of these two phenotypes is modified by different genes. Our findings set the stage for defining disease-related genetic pathways that will ultimately provide insight into disease mechanism. 相似文献
14.
Molecular features of the CAG repeats and clinical manifestation of Machado-Joseph disease 总被引:15,自引:3,他引:12
Maruyama Hirofumi; Nakamura Shigenobu; Matsuyama Zenjiro; Sakai Tetsuo; Doyu Manabu; Sobue Gen; Seto Makiko; Tsujihata Mitsuhiro; Oh-i Takekazu; Nishio Takeshi; Sunohara Nobuhiko; Takahashi Ryosuke; Hayashi Michiyuki; Nishino Ichizo; Ohtake Toshiyuki; Oda Tatsuro; Nishimura Masataka; Saida Takahiko; Matsumoto Hiroyuki; Baba Masayuki; Kawaguchi Yoshiya; Kakizuka Akira; Kawakami Hideshi 《Human molecular genetics》1995,4(5):807-812
Machado-Joseph disease (MJD) is an autosomal dominant spinocerebellardegeneration mapped to chromosome 14q32.1. The CAG expansionsof the MJD1 gene was identified as the cause of the disease.We have analyzed 90 MJD individuals from 62 independent MJDfamilies and found that the MJD1 repeat length is inverselycorrelated with the age of onset (r= 0.87). The MJD chromosomescontained 6184 repeat units, whereas normal chromosomesdisplayed 1434 repeats. In the normal chromosomes, 14repeat units were the most common and the shortest. In associationwith the clinical anticipation of the disease, a parent-childanalysis showed the unidirectional expansion of CAG repeatsand no case of diminution in the affected family. The differencesin CAG repeat length between parent and child and between siblingsare greater in paternal transmission than in maternal transmission.Detailed analysis revealed that a large degree of expansionwas associated with a shorter length of MJD1 gene in paternaltransmission. On the other hand, the increments of increasewere similar for shorter and longer expansion in maternal transmission.Among the three clinical subtypes, type I of MJD, with dystonia,showed a larger degree of expansion in CAG repeats of the geneand younger ages of onset than the other types. 相似文献
15.
Martins S Calafell F Wong VC Sequeiros J Amorim A 《European journal of human genetics : EJHG》2006,14(8):932-940
Despite the intense debate around the repeat instability reported on the large group of neurological disorders caused by trinucleotide repeat expansions, little is known about the mutation process underlying alleles in the normal range that, ultimately, expand to pathological size. In this study, we assessed the mutation mechanisms by which wild-type Machado-Joseph disease (MJD) alleles have been generated throughout human evolution. Haplotypes including the CAG repeat, six intragenic SNPs and four flanking microsatellites were analysed in 431 normal chromosomes of European, Asian and African origin. A bimodal CAG repeat length frequency distribution was found in the four most frequent wild-type lineages (H1-GCGGCA; H2-GTGGCA; H3-TTAGAC and H4-TTACAC). Based on flanking microsatellite haplotypes, the variance calculated by analysis of molecular variance between modal (CAG)n alleles was little or null in lineages H1, H2 and H4, as were the pairwise differences. Moreover, genetic distances among all the alleles from each lineage did not reflect the allele sizes differences, as expected if a stepwise mutation model was the main process of evolution. On the contrary, when exposed in maximum parsimonious phylogenetic trees, a large number of mutation steps separated same-size alleles, whereas several microsatellite haplotypes were shared by modal CAGs. In conclusion, our results suggest that the main mutation mechanism occurring in the evolution of the polymorphic CAG region at MJD/SCA3 locus is a multistep one, either by gene conversion or DNA slippage; repeats with 14, 21, 23 and 27 CAGs are the main alleles involved in this process. 相似文献
16.
Takiyama Y.; Igasrashi S.; Rogaeva E.A.; Endo K.; Rogaev E.I.; Tanaka H.; Sherrington R.; Sanpei K.; Liang Y.; Saito M.; Tsuda T.; Takano H.; Ikeda M.; Lin C.; Chi H.; Kennedy J. L.; Lang A. E.; Wherrett J.R.; Segawa M.; Nomura Y.; Yuasa T.; Weissenbach J.; Yoshida M.; Nishizawa M.; Kidd K.K.; Tsuji S.; St George-Hyslop P.H. 《Human molecular genetics》1995,4(7):1137-1146
The size of the (CAG)n repeat array in the 3' end of the MJDIgene and the haplotype at a series of microsateilite markerssurrounding the MJD1 gene were examined in a large cohort ofJapanese and Caucasian subjects affected with Machado-Josephdisease (MJD). Our data provide five novel observations. First,MJD is associated with expansion of the array from the normalrange of 1437 repeats to 6884 repeats in mostJapanese and Caucasian subjects, but no subjects were observedwith expansions intermediate in size between those of the normaland MJD affected groups. Second, the expanded allele associatedwith MJD displays inter-generational instability, particularlyin male meloses, and this instability was associated with theclinical phenomenon of anticipation. Third, the size of theexpanded allele is not only Inversely correlated with the age-of-onsetof MJD (r=0.738, p<0.001), but is also correlatedwith the frequency of other clinical features [e.g. pseudoexophthalmosand pyramidal signs were more frequent in subjects with largerrepeats (p<0.001 and p>0.05 respectively)]. Fourth, thedisease phenotype is significantly more severe and had an earlyage of onset (16 years) in a subject homozygous for the expandedallele, which contrasts with Huntington disease and suggeststhat the expanded allele in the MJD1 gene could exert its effecteither by a dominant negative effect (putatively excluded inHD) or by a gain of function effect as proposed for HD. Finally,Japanese and Caucasian subjects affected with MJD share haplotypesat several markers surrounding the MJD1 gene, which are uncommonin the normal Japanese and Caucasian population, and which suggeststhe existence either of common founders in these populationsor of chromosomes susceptible to pathologic expansion of theCAG repeat in the MJD1 gene. 相似文献
17.
Libby RT Monckton DG Fu YH Martinez RA McAbney JP Lau R Einum DD Nichol K Ware CB Ptacek LJ Pearson CE La Spada AR 《Human molecular genetics》2003,12(1):41-50
Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant cerebellar ataxia caused by a CAG repeat expansion in the ataxin-7 gene. In humans, SCA7 is characterized by marked anticipation due to intergenerational repeat instability with a bias toward expansion, and is thus regarded as the most unstable of the polyglutamine diseases. To study the molecular basis of CAG/CTG repeat instability and its pathological significance, we generated lines of transgenic mice carrying either a SCA7 cDNA construct or a 13.5 kb SCA7 genomic fragment with 92 CAG repeats. While the cDNA transgenic mice showed little intergenerational repeat instability, the genomic fragment transgenic mice displayed marked intergenerational instability with an obvious expansion bias. We then went on to generate additional lines of genomic fragment transgenic mice, and observed that deletion of the 3' genomic region significantly stabilized intergenerational transmission of the SCA7 CAG92 repeat. These results suggest that cis-information present on the genomic fragment is driving the instability process. As the SCA7 genomic fragment contains a large number of replication-associated motifs, the presence of such sequence elements may make the SCA7 CAG repeat region more susceptible to instability. Small-pool and standard PCR analysis of tissues from genomic fragment mice revealed large repeat expansions in their brains and livers, but no such changes were found in any tissues from cDNA transgenic mice that have been shown to undergo neurodegeneration. As large somatic repeat expansions are absent from the brains of SCA7 cDNA mice, our results indicate that neurodegeneration can occur without marked somatic mosaicism, at least in these mice. 相似文献
18.
19.
Length-dependent gametic CAG repeat instability in the Huntington's disease knock-in mouse 总被引:1,自引:0,他引:1
Wheeler VC; Auerbach W; White JK; Srinidhi J; Auerbach A; Ryan A; Duyao MP; Vrbanac V; Weaver M; Gusella JF; Joyner AL; MacDonald ME 《Human molecular genetics》1999,8(1):115-122
The CAG repeats in the human Huntington's disease (HD) gene exhibit
striking length-dependent intergenerational instability, typically small
size increases or decreases of one to a few CAGs, but little variation in
somatic tissues. In a subset of male transmissions, larger size increases
occur to produce extreme HD alleles that display somatic instability and
cause juvenile onset of the disorder. Initial efforts to reproduce these
features in a mouse model transgenic for HD exon 1 with 48 CAG repeats
revealed only mild intergenerational instability ( approximately 2% of
meioses). A similar pattern was obtained when this repeat was inserted into
exon 1 of the mouse Hdh gene. However, lengthening the repeats in Hdh to 90
and 109 units produced a graded increase in the mutation frequency to
>70%, with instability being more evident in female transmissions. No
large jumps in CAG length were detected in either male or female
transmissions. Instead, size changes were modest increases and decreases,
with expansions typically emanating from males and contractions from
females. Limited CAG variation in the somatic tissues gave way to marked
mosaicism in liver and striatum for the longest repeats in older mice.
These results indicate that gametogenesis is the primary source of
inherited instability in the Hdh knock-in mouse, as it is in man, but that
the underlying repeat length-dependent mechanism, which may or may not be
related in the two species, operates at higher CAG numbers. Moreover, the
large CAG repeat increases seen in a subset of male HD transmissions are
not reproduced in the mouse, suggesting that these arise by a different
fundamental mechanism than the small size fluctuations that are frequent
during gametogenesis in both species.
相似文献
20.
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