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1.
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
2.
The androgen receptor (AR) gene is located on the X chromosome and contains a polymorphic CAG tract. CAG repeat expansions in the AR have been associated with male infertility and the neuromuscular disease, spinal bulbar muscular atrophy (SBMA). Based on Mendelian inheritance patterns, moderate CAG expansions in infertile men treated by intracytoplasmic sperm injection (ICSI) would be vertically transmitted to female offspring. Should further elongation of the repeat region occur in the male germline, it is conceivable that longer expansions could also be transmitted by ICSI and may lead to an increased incidence of male infertility and SBMA in succeeding generations. To determine the degree of stability of the paternal AR CAG tract following ICSI, we compared the CAG repeat number in the AR alleles of 92 men presenting for ICSI and their 99 ICSI-conceived daughters. CAG repeat lengths in the AR alleles were determined by fluorescent polymerase chain reaction and Genescan analysis of amplification products separated on DNA sequencing gels. In the vast majority of cases (95 out of 99), we found that the AR CAG tracts ranging in size from 15-28 repeats exhibited stable inheritance in female offspring. However, in the remaining father-daughter pairs, there was a discordance in the expected inheritance pattern with evidence for both CAG expansion (20-->24; 22-->23) and contraction (26-->18 or 22) of the paternal AR allele. The detection of a low frequency of CAG mutation in paternal AR alleles following ICSI would be consistent with gonadal mosaicism originating from meiotic DNA replication errors. These findings in a typical group of infertile men undergoing ICSI for a variety of indications tend to alleviate concerns that ICSI may promote the transmission of AR alleles with expanded CAG tracts and suggest that the risk of SBMA in second generation sons would be extremely low. 相似文献
3.
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
4.
Gao R Matsuura T Coolbaugh M Zühlke C Nakamura K Rasmussen A Siciliano MJ Ashizawa T Lin X 《European journal of human genetics : EJHG》2008,16(2):215-222
Trinucleotide repeat expansions are dynamic mutations causing many neurological disorders, and their instability is influenced by multiple factors. Repeat configuration seems particularly important, and pure repeats are thought to be more unstable than interrupted repeats. But direct evidence is still lacking. Here, we presented strong support for this hypothesis from our studies on spinocerebellar ataxia type 17 (SCA17). SCA17 is a typical polyglutamine disease caused by CAG repeat expansion in TBP (TATA binding protein), and is unique in that the pure expanded polyglutamine tract is coded by either a simple configuration with long stretches of pure CAGs or a complex configuration containing CAA interruptions. By small pool PCR (SP-PCR) analysis of blood DNA from SCA17 patients of distinct racial backgrounds, we quantitatively assessed the instability of these two types of expanded alleles coding similar length of polyglutamine expansion. Mutation frequency in patients harboring pure CAG repeats is 2-3 folds of those with CAA interruptions. Interestingly, the pure CAG repeats showed both expansion and deletion while the interrupted repeats exhibited mostly deletion at a significantly lower frequency. These data strongly suggest that repeat configuration is a critical determinant for instability, and CAA interruptions might serve as a limiting element for further expansion of CAG repeats in SCA17 locus, suggesting a molecular basis for lack of anticipation in SCA17 families with interrupted CAG expansion. 相似文献
5.
Spinal and bulbar muscular atrophy (SBMA) is one of a growing number of neurodegenerative diseases caused by a polyglutamine-encoding CAG trinucleotide repeat expansion, and is caused by an expansion within exon 1 of the androgen receptor (AR) gene. The family of polyglutamine diseases is characterized by the presence of ubiquitinated, intranuclear inclusions associated with molecular chaperones and 26S proteasome components, although the role of these inclusions in the pathogenesis of polyglutamine diseases remains unclear. The over-expression of molecular chaperones of the Hsp70 and Hsp40 families has been shown to modulate inclusion frequency and cellular toxicity. We developed a cell culture system which enables the quantitative analysis of the effects of molecular chaperones on the biochemical properties of an expanded repeat AR. Using this approach, we demonstrate that Hsp70 and its co-chaperone Hsp40 not only increase expanded repeat AR solubility, but function to enhance the degradation of expanded repeat AR through the proteasome. Furthermore, our studies indicate that these molecular chaperones significantly decrease the half-life of an expanded repeat AR. Molecular chaperone enhancement of protein degradation points to the modulation of molecular chaperones as a potential therapeutic target for polyglutamine diseases. 相似文献
6.
In the past few years, a new type of genetic mutation, expansion of trinucleotide repeats, has been shown to cause neurologic disease. This new class of mutations was first identified in 1991 as the underlying genetic defect in spinal and bulbar muscular atrophy and the fragile X syndrome, and in recent years, trinucleotide repeat expansions have been found to be the causative mechanism in 10 other neurologic diseases. These mutations are produced by heritable unstable DNA and are termed “dynamic mutations” because of changes in the number of repeat units inherited from generation to generation. In the normal population, these repeat units, although polymorphic, are stably inherited. To date four types of trinucleotide repeat expansions have been identified: (1) long cytosine-guanine-guanine (CGG) repeats in the two fragile X syndromes (FRAXA and FRAXE), (2) long cytosine-thymine-guanine (CTG) repeat expansions in myotonic dystrophy, (3) long guanine-adenine-adenine repeat expansions in Friedreich's ataxia and (4) short cytosine-adenine-guanine repeat expansions (CAG) which are implicated in eight neurodegenerative disorders and are the focus of this review. Diseases that are caused by trinucleotide repeat expansions exhibit a phenomenon called anticipation that can not be explained by conventional Mendelian genetics. Anticipation is defined as increase in the severity of disease with an earlier age of onset of symptoms in successive generations [5, 50, 57, 106]. Anticipation is often influenced by the sex of the transmitting parent, and for most CAG repeat disorders, the disease is more severe when paternally transmitted. The severity and the age of onset of the disease have been correlated with the size of the repeats on mutant alleles, with the age of onset being inversely correlated with the size of the expansion. In all eight disorders caused by CAG repeat expansion, the repeat is located within the coding region of the gene involved and in all cases it is translated into a stretch of polyglutamines in the respective proteins. All the proteins are unrelated outside of the polyglutamine stretch and most are novel with exception of the androgen receptor and the voltage gated α1A calcium channel, which are mutated in spinal and bulbar muscular atrophy and spinocerebellar ataxia type 6. It is intriguing that the proteins are ubiquitously expressed in both peripheral and nervous tissue but in each disorder only a select population of nerve cells are targeted for degeneration as a consequence of the expanded CAG repeat. Current thinking among scientists working on the molecular mechanisms of neurodegeneration in these diseases is that the presence of an expanded polyglutamine confers a gain of function onto the involved protein. To understand the mechanisms underlying the pathogenesis of these diseases, investigators have turned to generating transgenic mice which recapitulate some of the features of the human disease and hence are excellent model systems to study the progression of the disease in vivo. 相似文献
7.
McManamny P Chy HS Finkelstein DI Craythorn RG Crack PJ Kola I Cheema SS Horne MK Wreford NG O'Bryan MK De Kretser DM Morrison JR 《Human molecular genetics》2002,11(18):2103-2111
Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease, caused by the expansion of a trinucleotide repeat (TNR) in exon 1 of the androgen receptor (AR) gene. This disorder is characterized by degeneration of motor and sensory neurons, proximal muscular atrophy, and endocrine abnormalities, such as gynecomastia and reduced fertility. We describe the development of a transgenic model of SBMA expressing a full-length human AR (hAR) cDNA carrying 65 (AR(65)) or 120 CAG repeats (AR(120)), with widespread expression driven by the cytomegalovirus promoter. Mice carrying the AR(120) transgene displayed behavioral and motor dysfunction, while mice carrying 65 CAG repeats showed a mild phenotype. Progressive muscle weakness and atrophy was observed in AR(120) mice and was associated with the loss of alpha-motor neurons in the spinal cord. There was no evidence of neurodegeneration in other brain structures. Motor dysfunction was observed in both male and female animals, showing that in SBMA the polyglutamine repeat expansion causes a dominant gain-of-function mutation in the AR. The male mice displayed a progressive reduction in sperm production consistent with testis defects reported in human patients. These mice represent the first model to reproduce the key features of SBMA, making them a useful resource for characterizing disease progression, and for testing therapeutic strategies for both polyglutamine and motor neuron diseases. 相似文献
8.
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
9.
SCA6 is caused by moderate CAG expansion in the alpha1A-voltage- dependent calcium channel gene 总被引:1,自引:3,他引:1
Riess O; Schols L; Bottger H; Nolte D; Vieira-Saecker AM; Schimming C; Kreuz F; Macek M Jr; Krebsova A; Macek M Sen; Klockgether T; Zuhlke C; Laccone FA 《Human molecular genetics》1997,6(8):1289-1293
Recently, moderate (CAG)>20 repeat expansions in the alpha1A-voltage-
dependent calcium channel gene (CACNL1A4) have been identified in a
previously unmapped type of SCA which has been named SCA6. We investigated
the (CAG)n repeat length of the CACNL1A4 gene in 733 patients with sporadic
ataxia and in 46 German families with dominantly inherited SCA which do not
harbor the SCA1, SCA2, or MJD1/SCA3 mutation, respectively. The SCA6 (CAG)n
expansion was identified in 32 patients most frequently with late
manifestation of the disease. The (CAG)n stretch of the affected allele
varied between 22 and 28 trinucleotide units and is therefore the shortest
trinucleotide repeat expansion causing spinocerebellar ataxia. The (CAG)n
repeat length is inversely correlated with the age at onset. In 11 parental
transmissions of the expanded allele no repeat instability has been
observed. Repeat instability was also not found for the normal allele
investigating 431 meioses in the CEPH families. Analyzing 248 apparently
healthy octogenerians revealed one allele of 18 repeats which is the
longest normal CAG repeat in the CACNL1A4 gene reported. The SCA6 mutation
causes the disease in approximately 10% of autosomal dominant SCA in
Germany. Most importantly, the trinucleotide expansion was observed in four
ataxia patients without obvious family history of the disease which
necessitates a search for the SCA6 (CAG)n expansion even in sporadic
patients.
相似文献
10.
Dadze S Wieland C Jakubiczka S Funke K Schröder E Royer-Pokora B Willers R Wieacker PF 《Molecular human reproduction》2000,6(3):207-214
The androgen receptor (AR) gene, located on the X-chromosome at Xq11-12, contains in exon 1 a polymorphic CAG repeat which codes for a polyglutamine tract. Contractions of the CAG repeat are said to be related to prostate cancer. In contrast, sizeable expansion of the CAG repeat can cause spinal and bulbar muscular atrophy (SBMA). In infertile patients of Chinese origin and in a Melbourne multinational population impaired sperm production has been postulated to be related to moderate expansions of the polyglutamine tract. In a study of a Swedish population of infertile patients these findings could not be corroborated. The aim of our investigation was to examine the correlation between the length of the CAG repeat and impaired sperm production in an infertile Caucasoid patient sample of German ethnic origin. We found no statistically significant relationship between the size of the CAG repeat or polyglutamine tract and idiopathic impaired sperm production in the population studied. The variability of the results by various investigators may be attributed to different ethnic origins and hence different genetic modifiers of the populations studied and/or to the high probability that these infertile males may represent a heterogeneous group with respect to the causes of defective spermatogenesis. 相似文献
11.
CAG repeat expansion in autosomal dominant pure spastic paraplegia linked to chromosome 2p21-p24 总被引:1,自引:2,他引:1
Nielsen JE; Koefoed P; Abell K; Hasholt L; Eiberg H; Fenger K; Niebuhr E; Sorensen SA 《Human molecular genetics》1997,6(11):1811-1816
CAG repeat expansions have been identified as the disease-causing dynamic
mutations in the coding regions of genes in several dominantly inherited
neurodegenerative disorders, including spinobulbar muscular atrophy,
Huntington's disease, dentatorubral-pallidoluysian atrophy, spinocerebellar
ataxia type 1, 2 and 6 and Machado-Joseph disease. The CAG repeat
expansions are translated to elongated polyglutamine tracts and an
increased size of the polyglutamine tract correlates with anticipation, the
cardinal feature, seen in all these diseases. Autosomal dominant pure
spastic peraplegia (ADPSP) is a degenerative disorder of the central motor
system clinically characterized by slowly progressive and unremitting
spasticity of the legs, hyperreflexia and Babinski's sign. Like the
established CAG repeat diseases ADPSP is characterized by both inter- and
intrafamilial variation and anticipation. Using the Repeat Expansion
Detection (RED) method, we have analyzed 21 affected individuals from six
Danish families with the disease linked to chromosome 2p21-p24. We found
that 20 of 21 affected individuals showed CAG repeat expansions versus two
of 21 healthy spouses, demonstrating a strongly statistically significant
association between the occurrence of the repeat expansion and the disease
(Fisher's test, P < 10(-5)) suggesting that a CAG repeat expansion is
involved presumably as a dynamic mutation in ADPSP linked to chromosome
2p21-p24. The size of the expansion is estimated to be > or = 60 CAG
repeat copies in the affected individuals. The CAG repeat expansion is very
likely translated and expressed as indicated by the detection of a
polyglutamine-containing protein in an ADPSP patient.
相似文献
12.
A. Ferlini M. C. Patrosso D. Guidetti L. Merlini A. Uncini M. Ragno R. Plasmati S. Fini M. Repetto P. Vezzoni A. Forabosco 《American journal of medical genetics. Part A》1995,55(1):105-111
An increase in the number of (CAG)n repeats in the first coding exon of the androgen receptor (AR) gene has been strongly associated with Kennedy disease (KD) (spinal and bulbar muscular atrophy). This is an X-linked hereditary disorder characterized by motoneuron degeneration occurring in adults together with gynecomastia and hyperestrogenemia. We have performed AR gene molecular analysis in several members of a large family with KD as well as in 25 sporadic patients suffering from heterogeneous motoneuron disease (MND). An increase in the length of the (CAG)n repeats was detected, as expected, in all the affected males and in obligatory carrier females, some of which had minor signs of lower motoneuron involvement. There was only one possible exception, one young male with initial signs of the disease, who had an apparent normal length allele. An increased pathological allele was also found in 3 patients with MND. This indicates that the analysis of (CAG)n repeats of the AR gene plays a role in the differential diagnosis of this heterogeneous group of neurological diseases. © 1995 Wiley-Liss, Inc. 相似文献
13.
Analysis of germline variation at the FMR1 CGG repeat shows variation in the normal-premutated borderline range 总被引:2,自引:2,他引:2
Mornet E; Chateau C; Hirst MC; Thepot F; Taillandier A; Cibois O; Serre JL 《Human molecular genetics》1996,5(6):821-825
In order to characterize the dynamics of CGG repeat instability at the
fragile X syndrome locus (FMR1 gene), we have used small pool PCR to
estimate the mutation rate within germline (sperm) and somatic tissue
(leukocytes) of two normal males, one carrying the most common 29 CGG
repeats allele, the other carrying a borderline normal-premutated allele of
55 repeats. Large contractions and moderate expansions of the repeat were
found in sperm and blood for the 55 repeat allele while almost no variation
was found in sperm or blood with the 29 repeat allele. Somatic blood DNA
exhibited fewer expansions and contractions than sperm. Contractions were
more frequent than expansions, and all the expansions were found in the +4
to +10 repeats range, while most of the contractions were found in the -10
to -30 range, suggesting that a subset of contractions results from a
distinct mechanism. These results also suggest that the dynamics of the CGG
repeat could be partly due to germline instability within the high normal
or premutated ranges.
相似文献
14.
Molecular and clinical correlations in autosomal dominant cerebellar ataxia with progressive macular dystrophy (SCA7) 总被引:11,自引:4,他引:11
David G; Durr A; Stevanin G; Cancel G; Abbas N; Benomar A; Belal S; Lebre AS; Abada-Bendib M; Grid D; Holmberg M; Yahyaoui M; Hentati F; Chkili T; Agid Y; Brice A 《Human molecular genetics》1998,7(2):165-170
Spinocerebellar ataxia 7 (SCA7) is caused by the expansion of an unstable
CAG repeat in the first exon of the SCA7 gene. We have analyzed the SCA7
mutation in 19 families and one isolated case of various geographical
origins, presenting with autosomal dominant cerebellar ataxia with
progressive macular dystrophy. The SCA7 CAG repeat was expanded in 77
patients and in 11 at-risk individuals, with alleles containing from 37 to
130 repeats, demonstrating that SCA7 is genetically homogeneous. Repeats on
normal alleles contained from 7 to 35 CAGs. There was a strong negative
correlation (r = -0.84) between the age at onset and the size of the CAG
repeat expansion in SCA7 patients. Larger expansions were associated with
earlier onset, a more severe and rapid clinical course, and a higher
frequency of decreased vision, ophthalmoplegia, extensor plantar response
and scoliosis. The frequency of other clinical signs such as dysphagia and
sphincter disturbances increased with disease duration. The mutation was
highly unstable during transmission, with a mean increase of 10 +/- 16 CAG
repeats, which was significantly greater in paternal (15 +/- 20) than in
maternal (5 +/- 5) transmissions. This correlated well with the marked
anticipation (19 +/- 13 years) observed in the families. Gonadal mosaicism,
observed in the sperm of a patient, was particularly important, with
expanded alleles ranging from 42 to >155 CAG repeats. The degree of
instability during transmission, resulting mostly in expansions, is greater
than in the seven other neurodegenerative disorders caused by polyglutamine
expansions.
相似文献
15.
Direct mutation analysis for Huntington disease (HD) became possible in 1993 with the identification of an expanded CAG trinucleotide repeat as the mutation underlying the disease. Expansion of CAG length beyond 35 repeats may be associated with the clinical presentation of HD. HD has never been seen in a person with a CAG size of <36 repeats. Intermediate alleles are defined as being below the affected CAG range but have the potential to expand to >35 CAG repeats within one generation. Thus, children of intermediate allele carriers have a low risk of developing HD. Currently, the intermediate allele range for HD is between 27 and 35 CAG repeats. In this study, we review the current knowledge on intermediate alleles for HD including the CAG repeat range, the intermediate allele frequency, and the clinical implications of an intermediate allele predictive test result. The factors influencing CAG repeat expansion, including the CAG size of the intermediate allele, the sex and age of the transmitting parent, the family history, and the HD gene sequence and haplotype, will also be reviewed. 相似文献
16.
Sato T; Oyake M; Nakamura K; Nakao K; Fukusima Y; Onodera O; Igarashi S; Takano H; Kikugawa K; Ishida Y; Shimohata T; Koide R; Ikeuchi T; Tanaka H; Futamura N; Matsumura R; Takayanagi T; Tanaka F; Sobue G; Komure O; Takahashi M; Sano A; Ichikawa Y; Goto J; Kanazawa I 《Human molecular genetics》1999,8(1):99-106
Dentatorubral-pallidoluysian atrophy (DRPLA) is one among an increasing
number of hereditary neurodegenerative diseases determined as being caused
by unstable expansion of CAG repeats coding for polyglutamine stretches. To
investigate the molecular mechanisms underlying CAG repeat instability, we
established three transgenic lines each harboring a single copy of a
full-length human mutant DRPLA gene carrying a CAG repeat expansion. These
transgenic mice exhibited an age- dependent increase (+0.31 per year) in
male transmission and an age- dependent contraction (-1.21 per year) in
female transmission. Similar tendencies in intergenerational instabilities
were also observed in human DRPLA parent-offspring pairs. The
intergenerational instabilities of the CAG repeats may be interpreted as
being derived from the instability occurring during continuous cell
division of spermatogonia in the male, and that occurring during the period
of meiotic arrest in the female. The transgenic mice also exhibited an
age-dependent increase in the degree of somatic mosaicism which occurred in
a cell lineage-dependent manner, with the size range of CAG repeats being
smaller in the cerebellum than in other tissues including the cerebrum,
consistent with observations in autopsied tissues of DRPLA patients. Thus,
the transgenic mice described in this study exhibited age- dependent
intergenerational as well as somatic instabilities of expanded CAG repeats
comparable with those observed in human DRPLA patients, and are therefore
expected to serve as good models for investigating the molecular mechanisms
of instabilities of CAG repeats.
相似文献
17.
Expression of unstable translated CAG repeats is the mutational mechanism in nine different neurodegenerative disorders. Although the products of genes harboring these repeats are widely expressed, a subset of neurons is vulnerable in each disease accounting for the different phenotypes. Somatic instability of the expanded CAG repeat has been implicated as a factor mediating the selective striatal neurodegeneration in Huntington disease. It remains unknown, however, whether such a mechanism contributes to the selective neurodegeneration in other polyglutamine diseases or not. To address this question, we investigated the pattern of CAG repeat instability in a knock-in mouse model of spinocerebellar ataxia type 1 (SCA1). Small pool PCR analysis on DNA from various neuronal and non-neuronal tissues revealed that somatic repeat instability was most remarkable in the striatum. In the two vulnerable tissues, cerebellum and spinal cord, there were substantial differences in the profiles of mosaicism. These results suggest that in SCA1 there is no clear causal relationship between the degree of somatic instability and selective neuronal vulnerability. The finding that somatic instability is most pronounced in the striatum of various knock-in models of polyglutamine diseases highlights the role of trans-acting tissue- or cell-specific factors in mediating the instability. 相似文献
18.
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
19.
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
20.
David C. Rubinsztein Jayne Leggo Timothy J. Crow Lynn E. DeLisi Cathy Walsh Sanjeev Jain Eugene S. Paykel 《American journal of medical genetics. Part A》1996,67(5):495-498
A new class of disease (including Huntington disease, Kennedy disease, and spinocerebellar ataxias types 1 and 3) results from abnormal expansions of CAG trinucleotides in the coding regions of genes. In all of these diseases the CAG repeats are thought to be translated into polyglutamine tracts. There is accumulating evidence arguing for CAG trinucleotide expansions as one of the causative disease mutations in schizophrenia and bipolar affective disorder. We and others believe that the TATA-binding protein (TBP) is an important candidate to investigate in these diseases as it contains a highly polymorphic stretch of glutamine codons, which are close to the threshold length where the polyglutamine tracts start to be associated with disease. Thus, we examined the lengths of this polyglutamine repeat in normal unrelated East Anglians, South African Blacks, sub-Saharan Africans mainly from Nigeria, and Asian Indians. We also examined 43 bipolar affective disorder patients and 65 schizophrenic patients. The range of polyglutamine tract-lengths that we found in humans was from 26–42 codons. No patients with bipolar affective disorder and schizophrenia had abnormal expansions at this locus. © 1996 Wiley-Liss, Inc. 相似文献