共查询到20条相似文献,搜索用时 31 毫秒
1.
Eliana Marisa Ramos Tammy Gillis Jayalakshmi S. Mysore Jong‐Min Lee Martin Gögele Yuri D'Elia Irene Pichler Jorge Sequeiros Peter P. Pramstaller James F. Gusella Marcy E. MacDonald Isabel Alonso 《American journal of medical genetics. Part B, Neuropsychiatric genetics》2015,168(2):135-143
Huntington's disease (HD) is a neurodegenerative disorder characterized by involuntary choreic movements, cognitive impairment, and behavioral changes, caused by the expansion of an unstable CAG repeat in HTT. We characterized the genetic diversity of the HD mutation by performing an extensive haplotype analysis of ~1Mb region flanking HTT in over 300 HD families of Portuguese origin. We observed that haplotype A, marked by HTT delta2642, was enriched in HD chromosomes and carried the two largest expansions reported in the Portuguese population. However, the most frequent HD haplotype B carried one of the largest (+12 CAGs) expansions, which resulted in an allele class change to full penetrance. Despite having a normal CAG distribution skewed to the higher end of the range, these two core haplotypes had similar expanded CAG repeat sizes compared to the other major core haplotypes (C and D) and there was no statistical difference in transmitted repeat instability across haplotypes. We observed a diversity of HTT region haplotypes in both normal and expanded chromosomes, representative of more than one ancestral chromosome underlying HD in Portugal, where multiple independent events on distinct chromosome 4 haplotypes have given rise to expansion into the pathogenic range. © 2015 Wiley Periodicals, Inc. 相似文献
2.
Martins S Matamá T Guimarães L Vale J Guimarães J Ramos L Coutinho P Sequeiros J Silveira I 《European journal of human genetics : EJHG》2003,11(10):808-811
Dentatorubropallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder characterized by a variable combination of progressive ataxia, epilepsy, myoclonus, choreoathetosis and dementia. This disease is caused by a (CAG)(n) expansion in the DRPLA gene, on chromosome 12p13. DRPLA is prevalent in Japan, but several families of non-Japanese ancestry have already been published. To identify the origin of expanded alleles in Portuguese families with DRPLA, we studied two previously reported intragenic SNPs in introns 1 and 3, in addition to the CAG repeat of the DRPLA gene. The results showed that all four Portuguese DRPLA families shared the same haplotype, which is also common to that reported for Japanese DRPLA chromosomes. This haplotype is also the most frequent in Japanese normal alleles, whereas it was rare in Portuguese control chromosomes. Thus, our findings support that a founder DRPLA haplotype of Asian origin was introduced in Portugal, being responsible for the frequency of the disease in this country. 相似文献
3.
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
4.
Evidence of a Common Founder for SCA12 in the Indian Population 总被引:1,自引:0,他引:1
S. Bahl K. Virdi U. Mittal M. P. Sachdeva A. K. Kalla S. E. Holmes E. O'Hearn R. L. Margolis S. Jain † A. K. Srivastava M. Mukerji ‡ 《Annals of human genetics》2005,69(5):528-534
Spinocerebellar ataxia type 12 (SCA12) is an autosomal dominant cerebellar ataxia associated with the expansion of an unstable CAG repeat in the 5′ region of the PPP2R2B gene on chromosome 5q31–5q32. We found that it accounts for ~16% (20/124) of all the autosomal dominant ataxia cases diagnosed in AIIMS, a major tertiary referral centre in North India. The length of the expanded allele in this population ranges from 51–69 CAG triplets. Interestingly, all the affected families belong to an endogamous population, which originated in the state of Haryana, India. We identified four novel SNPs and a dinucleotide marker spanning ~137 kb downstream of CAG repeat in the PPP2R2B gene. Analysis of 20 Indian SCA12 families and ethnically matched normal unrelated individuals revealed one haplotype to be significantly associated with the affected alleles (P= 0.000), clearly indicating the presence of a common founder for SCA12 in the Indian population. This haplotype was not shared by the American pedigree with SCA12. Therefore, the SCA12 expansion appears to have originated at least twice. 相似文献
5.
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
6.
Analysis of the dynamic mutation in the SCA7 gene shows marked parental effects on CAG repeat transmission 总被引:2,自引:3,他引:2
Gouw LG; Castaneda MA; McKenna CK; Digre KB; Pulst SM; Perlman S; Lee MS; Gomez C; Fischbeck K; Gagnon D; Storey E; Bird T; Jeri FR; Ptacek LJ 《Human molecular genetics》1998,7(3):525-532
The gene for spinocerebellar ataxia 7 (SCA7) includes a transcribed,
translated CAG tract that is expanded in SCA7 patients. We have determined
expansions in 73 individuals from 17 SCA7 kindreds and compared them with
repeat lengths of 180 unaffected individuals. Subjects with abnormal
expansions comprise 59 clinically affected individuals and 14 at-risk
currently unaffected individuals predicted to carry the mutation by
haplotype analysis. For expanded alleles, CAG repeat length correlates with
disease progression and severity and correlates inversely with age of
onset. Increased repeat lengths are seen in generational transmission of
the disease allele, consistent with the pattern of clinical anticipation
seen in these kindreds. Repeat lengths in expanded alleles show somatic
mosaicism in leukocyte DNA, suggesting that these alleles are unstable
within individuals as well as between generations. Although dynamic repeat
expansions from paternal transmissions are greater than those from maternal
transmissions, maternal transmission of disease is more common, suggesting
germline or embryonic effects of the repeat expansion.
相似文献
7.
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
8.
SCA8 CTG repeat: en masse contractions in sperm and intergenerational sequence changes may play a role in reduced penetrance 总被引:2,自引:0,他引:2
We recently described an untranslated CTG expansion that causes a previously undescribed form of spinocerebellar ataxia (SCA8). The SCA8 CTG repeat is preceded by a polymorphic but stable CTA tract, with the configuration (CTA)(1-21)(CTG)(n). The CTG portion of the repeat is elongated on pathogenic alleles, which nearly always change in size when transmitted from generation to generation. To better understand the reduced penetrance and maternal penetrance bias associated with SCA8 we analyzed the sequence configurations and instability patterns of the CTG repeat in affected and unaffected family members. In contrast to other triplet repeat diseases, expanded alleles found in affected SCA8 individuals can have either a pure uninterrupted CTG repeat tract or an allele with one or more CCG, CTA, CTC, CCA or CTT interruptions. Surprisingly, we found six different sequence configurations of the CTG repeat on expanded alleles in a seven generation family. In two instances duplication of CCG interruptions occurred over a single generation and in other instances duplications that had occurred in different branches of the family could be inferred. We also evaluated SCA8 instability in sperm samples from individuals with expansions ranging in size from 80 to 800 repeats in blood. Surprisingly the SCA8 repeat tract in sperm underwent contractions, with nearly all of the resulting expanded alleles having repeat lengths of <100 CTGs, a size that is not often associated with disease. These en masse repeat contractions in sperm likely underlie the reduced penetrance associated with paternal transmission. 相似文献
9.
I. Silveira P. Coutinho P. Maciel C. Gaspar S. Hayes A. Dias J. Guimares L. Loureiro J. Sequeiros G.A. Rouleau 《American journal of medical genetics. Part A》1998,81(2):134-138
The spinocerebellar ataxias (SCAs) are clinically and genetically a heterogeneous group of neurodegenerative disorders. To date, eight different loci causing SCA have been identified: SCA1, SCA2, Machado-Joseph disease (MJD)/SCA3, SCA4, SCA5, SCA6, SCA7, and dentatorubropallidoluysian atrophy (DRPLA). Expansion of a CAG repeat in the disease genes has been found in five of these disorders. To estimate the relative frequencies of the SCA1, DRPLA, MJD, SCA2, and SCA6 mutations among Portuguese ataxia patients, we collected DNA samples from 48 ataxia families and performed polymerase chain reaction (PCR) amplification of the CAG repeat mutations on chromosomes 6p, 12p, 14q, 12q, and 19p, respectively. Fifty-five individuals belonging to 34 dominant families (74%) had an expanded CAG repeat at the MJD gene. In five individuals from two kindreds with a dominant pattern of inheritance (4%), an expanded CAG repeat at the SCA2 gene was found. In MJD patients, the normal allele size ranged from 13 to 41, whereas the mutant alleles contained 65 to 80 repeats. For the SCA2 patients, normal alleles had 22 or 23, while expanded alleles had between 36 and 47 CAG units. We did not find the SCA1, DRPLA, or SCA6 mutations in our group of families. The MJD mutation remains the most common cause of SCA in Portugal, while a small number of cases are caused by mutations at the SCA2 gene, and 22% are due to still unidentified genes. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:134–138, 1998. © 1998 Wiley-Liss, Inc. 相似文献
10.
Stevanin G; Giunti P; Belal GDS; Durr A; Ruberg M; Wood N; Brice A 《Human molecular genetics》1998,7(11):1809-1813
Spinocerebellar ataxia 7 (SCA7) is the eighth neurodegenerative disorder
caused by a translated CAG repeat expansion. Normal SCA7 alleles carry from
four to 35 CAG repeats, whereas pathological alleles carry from 37 to
approximately 200. Intermediate alleles (IAs), with 28- 35 repeats in the
SCA7 gene are exceedingly rare in the general population and are not
associated with the SCA7 phenotype, although they have been found among
relatives of four SCA7 families. In two of these families, IAs bearing 35
and 28 CAG repeats gave rise, during paternal transmission, to SCA7
expansions of 57 and 47 repeats, respectively, that were confirmed by
haplotype reconstructions in one case and by inference in the other.
Furthermore, the four haplotypes segregating with IAs were identical to the
expanded alleles in each kindred, but differed among the families,
indicating multiple origins of the SCA7 mutation in these families with
different geographical origins. Our results provide the first evidence of
de novo SCA7 expansions from IAs that are not associated with the phenotype
but can expand to the pathological range during some paternal
transmissions. IAs that segregate in unaffected branches of the pedigrees
might, therefore, constitute a reservoir for future de novo mutations that
occur in a recurrent but random manner. This would explain the persistence
of the disease in spite of the great anticipation (approximately 20
years/generation) characteristic of SCA7. So far, de novo expansions among
the disorders caused by polyglutamine repeats have only been demonstrated
in Huntington's disease.
相似文献
11.
Craig K Takiyama Y Soong BW Jardim LB Saraiva-Pereira ML Lythgow K Morino H Maruyama H Kawakami H Chinnery PF 《European journal of human genetics : EJHG》2008,16(7):841-847
Spinocerebellar ataxia type 6 (SCA6) is a common cause of dominantly inherited ataxia due to an expansion of the CAG repeat in the CACNA1A gene. Affected individuals from the same population share a common haplotype, raising the possibility that most SCA6 cases have descended from a small number of common founders across the globe. To test this hypothesis, we carried out haplotype analysis on SCA6 families from Europe, South America and the Far East, including an established de novo SCA6 expansion. A core CACNA1A disease haplotype was found in affected individuals across the globe. This was also present in the unaffected father of the de novo case, suggesting that the shared chromosome predisposes to the CAG repeat expansion at the SCA6 locus. The SCA6 expansion lies within a CpG island, which could act as a cis-acting element predisposing to repeat expansion as for other CAG/CTG repeat diseases. Polymorphic variation in this region may explain the high-risk haplotype found in SCA6 families. 相似文献
12.
O. Didierjean G. Cancel G. Stevanin A. Durr K. Burk A. Benomar A. Lezin S. Belal M. Abada-Bendid T. Klockgether A. Brice 《Journal of medical genetics》1999,36(5):415-417
Spinocerebellar ataxia type 2 (SCA2) is caused by the expansion of an unstable CAG repeat encoding a polyglutamine tract. Repeats with 32 to 200 CAGs are associated with the disease, whereas normal chromosomes contain 13 to 33 repeats. We tested 220 families of different geographical origins for the SCA2 mutation. Thirty three were positive (15%). Twenty three families with at least two affected subjects were tested for linkage disequilibium (LD) between the SCA2 mutation and three microsatellite markers, two of which (D12S1332-D12S1333) closely flanked the mutation; the other (D12S1672) was intragenic. Many different haplotypes were observed, indicating the occurrence of several ancestral mutations. However, the same haplotype, not observed in controls, was detected in the German, the Serbian, and some of the French families, suggesting a founder effect or recurrent mutations on an at risk haplotype. 相似文献
13.
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
14.
Screening for proteins with polyglutamine expansions in autosomal dominant cerebellar ataxias 总被引:2,自引:8,他引:2
Stevanin G; Trottier Y; Cancel G; Durr A; David G; Didierjean O; Burk K; Imbert G; Saudou F; Abada-Bendib M; Gourfinkel-An I; Benomar A; Abbas N; Klockgether T; Grid D; Agid Y; Mandel JL; Brice A 《Human molecular genetics》1996,5(12):1887-1892
Expansion of trinucleotide CAG repeats coding for polyglutamine has been
implicated in five neurodegenerative disorders, including spinocerebellar
ataxia (SCA) 1 and SCA3 or Machado-Joseph disease (SCA3/MJD), two forms of
type I autosomal dominant cerebellar ataxias (ADCA). Using the 1C2 antibody
which specifically recognizes large polyglutamine tracts, particularly
those that are expanded, we recently reported the detection of proteins
with pathological glutamine expansions in lymphoblasts from another form of
ADCA type I, SCA2, as well as from patients presenting with the distinct
phenotype of ADCA type II. We now have screened a large series of patients
with ADCA or isolated cases with cerebellar ataxia, for the presence of
proteins with polyglutamine expansions. A 150 kDa SCA2 protein was detected
in 16 out of 40 families with ADCA type I. This corresponds to 24% of all
ADCA type I families, which is much more frequent than SCA1 in this series
of patients (13%). The signal intensity of the SCA2 protein was negatively
correlated to age at onset, as expected for an expanded and unstable
trinucleotide repeat mutation. The disease segregated with markers closely
linked to the SCA2 locus in all identified SCA2 families. In addition, a
specific 130 kDa protein, which segregated with the disease, was detected
in lymphoblasts of patients from nine families with ADCA type II. It was
also visualized in the cerebral cortex of one of the patients,
demonstrating its translation in the nervous system. Finally, no new
disease-related proteins containing expanded polyglutamine tracts could be
detected in lymphoblasts from the remaining patients with ADCA or isolated
cases with cerebellar ataxia.
相似文献
15.
遗传性脊髓小脑型共济失调的CAG三核苷酸突变检测 总被引:18,自引:5,他引:13
目的 评价SCA1、SCA2、SCA3/MjD、SCA6、SCA7和DRPLA的CAG三核苷酸异常扩增突变「(CAG)n」,在中国人遗传性脊髓小脑型共济失调(spinocerebellar ataxia,SCA)患者的分布频率。方法 经聚合酶链反应、变性聚丙烯酰按凝胶电泳和银染显带技术,检测分析了85个中国人常染色体显性遗传SCA家系(其中患者167例)和37例散发SCA患者的SCA1、SCA2、 相似文献
16.
Verbeek DS Piersma SJ Hennekam EF Ippel EF Pearson PL Sinke RJ 《European journal of human genetics : EJHG》2004,12(6):441-446
This pilot study was initiated to show the existence of founder effects in the Dutch autosomal dominant cerebellar ataxia (ADCA) population. The ADCAs comprise a clinically heterogeneous group of neurodegenerative disorders and the estimated prevalence in the Netherlands is approximately 3:100 000 individuals. Here, we focused on the SCA3 and SCA6 genes because mutations in these genes occur most frequently in the Netherlands. We were able to determine a common origin of the CAG repeat expansions in the majority of Dutch SCA3 and SCA6 families. Haplotype analysis and linkage disequilibrium studies with polymorphic markers revealed shared haplotypes surrounding the SCA3 and SCA6 genes. These results strongly suggest that ADCA families can be traced back to common ancestors in particular parts of the Netherlands. 相似文献
17.
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
18.
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
19.
20.
A Complete Association of an intronic SNP rs6798742 with Origin of Spinocerebellar Ataxia Type 7‐CAG Expansion Loci in the Indian and Mexican Population 下载免费PDF全文
Mohammed Faruq Jonathan J. Magaña Varun Suroliya Ankita Narang Nadia M. Murillo‐Melo Oscar Hernández‐Hernández Achal K. Srivastava Mitali Mukerji 《Annals of human genetics》2017,81(5):197-204