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1.
Pornprot Limprasert Nassim Nouri Chamnong Nopparatana Prescott L. Deininger Bronya J.B. Keats 《American journal of medical genetics. Part A》1997,74(5):488-493
The CAG repeat tract at the autosomal dominant spinocerebellar ataxia type 1 (SCA1) locus was analyzed in SCA1 families and French-Acadian, African-American, Caucasian, Greenland Inuit, and Thai populations. The normal alleles had 9–37 repeats, whereas disease alleles contained 44–64 repeats. The CAG repeat tract contained one or two CAT interruptions in 44 of 47 normal human chromosomes and in all five chimpanzees examined. In contrast, no CAT interruptions were found in Old World monkeys or expanded human alleles. The number and positions of CAT interruptions may be important in stabilizing CAG repeat tracts in normal chromosomes. At least five codons occupy the region corresponding to the polyglutamine tract at the SCA1 locus in mice, rats, and other rodents. They comprise three or four CCN (coding for proline) in addition to one or two CAG repeats. Am. J. Med. Genet. 74:488–493, 1997. © 1997 Wiley-Liss, Inc. 相似文献
2.
Gossen M; Schmitt I; Obst K; Wahle P; Epplen JT; Riess O 《Human molecular genetics》1996,5(3):381-389
Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disorder caused
by an expanded and unstable (CAG) > 40 repeat within a gene of unknown
function. We isolated the complete coding region of the rat SCA1 gene
(rsca1), the 5'-untranslated region (UTR) and 1.3 kb of the 3'-UTR. The rat
sequence exhibits 90% peptide identity to the human counterpart. In
comparison to human, the rat (CAG)n block is reduced to two trinucleotide
motifs preceded by three different proline codons not present in man.
Furthermore, we investigated the expression of rsca1 in different rat
tissues. The rsca1 gene is predominantly expressed in brain throughout all
developmental stages. In situ hybridizations reveal high levels of
expression in various regions of the adult rat brain, including cerebellum,
hippocampus and cortex.
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3.
Analysis of spinocerebellar ataxia type 2 gene and haplotype analysis: (CCG)1-2 polymorphism and contribution to founder effect
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Mizushima K Watanabe M Kondo I Okamoto K Shizuka M Abe K Aoki M Shoji M 《Journal of medical genetics》1999,36(2):112-114
Spinocerebellar ataxia type 2 is a familial spinocerebellar ataxia with autosomal dominant inheritance. The gene responsible was recently cloned and this disorder was found to be the result of a CAG expansion in its open reading frame. We analysed 13 SCA2 patients in seven unrelated families in Gunma Prefecture, Japan. In four of the seven families, we detected CCG or CCGCCG interruptions in only the expanded alleles. Cosegregation of these polymorphisms with SCA2 patients was established within each family. Together with the results of haplotype analyses, we considered that at least two founders were present in our area and that these (CCG)1-2 polymorphisms may make analysis of founder effects easier. By sequencing analysis we found that although the number of the long CAG repeat varied in each subclone of expanded alleles, these polymorphisms did not change their configuration. This finding suggests that CCG or CCGCCG sequences are stable when surrounded by the long CAG repeat and a single CAG. Moreover, the presence of these polymorphisms may lead to miscounting the repeat size by conventional estimation using a size marker such as an M13 sequencing ladder. Therefore we should consider these polymorphisms and accurately determine the repeat size by sequencing. 相似文献
4.
Rüb U Brunt ER Gierga K Schultz C Paulson H de Vos RA Braak H 《Journal of chemical neuroanatomy》2003,25(2):115-127
The nucleus raphe interpositus (RIP) plays an important role in the premotor network for saccades. Its omnipause neurons gate the activity of the burst neurons for vertical saccades lying within the rostral interstitial nucleus of the medial longitudinal fascicle and that for horizontal saccades residing in the caudal subnucleus of the pontine reticular formation. In the present study we investigated the RIP in five patients with clinically diagnosed and genetically confirmed spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease. Polyethylene glycol-embedded 100 microm serial sections stained for lipofuscin pigment and Nissl material as well as paraffin-embedded Nissl stained thin sections revealed the hitherto overlooked involvement of this pontine nucleus in the degenerative process underlying SCA3, whereby in four of our SCA3 patients the RIP underwent a conspicuous loss of presumed omnipause neurons. As observed in other affected brain structures, the RIP of all our SCA3 patients displayed reactive astrocytes and activated microglial cells, while some of the few of its surviving neurons harbored an ataxin-3-immunopositive intranuclear inclusion body. The findings of the present pathoanatomical study suggest that (1) neurodegeneration in the brain stem of terminal SCA3 patients is more widespread than previously thought and is not confined to cranial nerve nuclei involved in the generation of saccades but likewise involves the premotor network for saccades and (2) damage to the RIP may contribute to slowing of horizontal saccades in SCA3 patients but is not associated with saccadic oscillations as occasionally speculated. 相似文献
5.
No association of the SCA1 (CAG)31 allele with Huntington's disease, myotonic dystrophy type 1 and spinocerebellar ataxia type 3 总被引:1,自引:0,他引:1
Trinucleotide repeat expansions are the underlying mutation in several neurodegenerative and neuromuscular disorders including at least eight spinocerebellar ataxias (SCA). The molecular mechanisms of repeat expansion are as yet insufficiently understood. Recently, an association of the SCA1 (CAG)31 repeat allele with Huntington's disease and myotonic dystrophy type 1 was described. These findings implicate a possible role of the SCA1 (CAG)31 allele in other triplet diseases. We analyzed the SCA1 CAG repeat length in a large sample of Huntington's disease (n=182), myotonic dystrophy type 1 (n=64) and SCA3 (n=31) patients. In none of these groups was a significant association with the 31 repeat allele found. Our findings do not support the hypothesis that this allele is involved in the etiology of trinucleotide expansion. 相似文献
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目的 探讨浙江沿海脊髓小脑性共济失调的基因突变检测与临床表现.方法 对该家系18例患者的临床表现、头颅MRI等辅助检查资料分析,并与10名家系中未发病成员及12名非血缘的健康人进行SCA31MJD基因CAG三核苷酸重复数目比较.结果 家系18例患者均为SCA3/MJD型,同时检测出家系中未发病对照组有2例为SCA31MJD型基因携带者.产物测序结果家系对照组与健康对照组CAG重复数为14~27次;SCA患者CAG重复数为67~82次;SCA3/MJD携带者CAG重复数为28~45次.在现存三代18例患者中,每代均有患者,男女均受累,起病年龄平均38岁,以行走不稳、动作笨拙和言语含糊为突出表现,MRI检测结果小脑、脑干明显萎缩.结论 在我国沿海存在SCA3/MJD家系遗传.临床均以共济失调和构音障碍为突出,CAG重复数目检测可为基因诊断和症状前诊断提供依据. 相似文献
8.
Genetic and clinical analysis of spinocerebellar ataxia type 8 repeat expansion in Yugoslavia 总被引:1,自引:0,他引:1
Topisirovic I Dragasevic N Savic D Ristic A Keckarevic M Keckarevic D Culjkovic B Petrovic I Romac S Kostic VS 《Clinical genetics》2002,62(4):321-324
Spinocerebellar ataxia type 8 (SCA8) is a slowly progressive ataxia causally associated with untranslated CTG repeat expansion on chromosome 13q21. However, the role of the CTG repeat in SCA8 pathology is not yet well understood. Therefore, we studied the length of the SCA8 CTA/CTG expansions (combined repeats, CRs) in 115 patients with ataxia, 64 unrelated individuals with non-triplet neuromuscular diseases, 70 unrelated patients with schizophrenia, and 125 healthy controls. Only one patient with apparently sporadic ataxia was identified with an expansion of 100 CRs. He had inherited the expansion from his asymptomatic father (140 CRs) and transmitted the mutation to his son (92 CRs). Paternal transmission in this family produced contractions of 40 and 8 CRs, respectively. None of the subjects from other studied groups had an expansion at the SCA8 locus. In the control group the number of CRs at the SCA8 locus ranged from 14 to 34. Our findings support the notion that allelic variants of the expansion mutation at the SCA8 locus can predispose to ataxia. 相似文献
9.
Matilla T.; Volpinl V.; Genis D.; Rosell J.; Corral J.; Davalos A.; Molins A.; Estivill X. 《Human molecular genetics》1993,2(12):2123-2128
Autosomal dominant cerebellar ataxia type 1 (ADCA1) is a clinicaland genetic heterogeneous neurodegenerative disorder which leadsto progressive cerebellar ataxia. One defective gene responsiblefor the disease was first localised to 6p (SCA1, splnocerebellarataxia type 1) and the mutation has been more recently characterised.We have analysed the CAG-repeat mutation responsible for theSCA1 phenotype in a large Spanish kindred with 41 affected members,in which positive linkage with D6S89 was previously shown. All(10) clinically affected members analysed were heterozygouswith one disease allele being between 41 to 57 CAG repeats,and the other in the normal range, from 6 to 39 repeats. Nineclinically unaffected individuals who were between the agesof 18 and 40, were found to have expansions of the CAG repeat(41 to 59), and 22 other at risk individuals werefound to have inherited the SCA1 gene with copies of the CAGrepeat in the normal range. We have also observed that affectedfathers passed on the mutated SCA1 gene with larger increasesin the number of CAG repeats than affected mothers did. In onecase a decrease in the number of CAG repeats (51 to 50) wasdetected in the transmission from the affected mother, and intwo cases no change was observed in the transmission of a 41allele repeat by a mother. As in the other disorders in whichknowledge of the mutation has been obtained, analysis of therepeat expansion dramatically changes diagnosis of SCA1. 相似文献
10.
Kato T Tanaka F Yamamoto M Yosida E Indo T Watanabe H Yoshiwara T Doyu M Sobue G 《Clinical genetics》2000,58(1):69-73
Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease caused by a CAG repeat expansion in the CACNA1A gene. The neurodegeneration that occurs in CAG repeat diseases is considered to share a common mechanism that may result in the gain of a toxic function related to the expanded polyglutamine tracts. However, the phenotypic expression in homozygotes for CAG repeat diseases has been controversial, and is not clearly related to a gain of functional mechanism. We identified a Japanese family with two sisters who were homozygous for the SCA6 with identical CAG repeat expansion (25/25). They showed an earlier age of onset (27 years in both) than their father (44 years), a heterozygote with an expanded allele showing the same CAG repeat length as the homozygotes (25/14). Interestingly, the two sisters showed differences in disease progression and severity, although the age of onset and CAG repeat length were identical. These findings strongly suggest that the gene dosage influences the age of onset, but other unknown factors are also important in the phenotypic expression of homozygous SCA6. 相似文献
11.
Gehrking KM Andresen JM Duvick L Lough J Zoghbi HY Orr HT 《Human molecular genetics》2011,20(11):2204-2212
Spinocerebellar ataxia type 1 (SCA1) is one of nine dominantly inherited neurodegenerative diseases caused by polyglutamine tract expansion. In SCA1, the expanded polyglutamine tract is in the ataxin-1 (ATXN1) protein. ATXN1 is part of an in vivo complex with retinoid acid receptor-related orphan receptor alpha (Rora) and the acetyltransferase tat-interactive protein 60 kDa (Tip60). ATXN1 and Tip60 interact directly via the ATXN1 and HMG-box protein 1 (AXH) domain of ATXN1. Moreover, the phospho-mimicking Asp amino acid at position 776, previously shown to enhance pathogenesis, increases the ability of ATXN1 to interact with Tip60. Using a genetic approach, the biological relevance of the ATXN1/Tip60 interaction was assessed by crossing ATXN1[82Q] mice with Tip60(+/-)animals. Partial Tip60 loss increased Rora and Rora-mediated gene expression and delayed ATXN1[82]-mediated cerebellar degeneration during mid-stage disease progression. These results suggested a specific, temporal role for Tip60 during disease progression. We also showed that genetic background modulated ATXN1[82Q]-induced phenotypes. Of interest, these latter studies showed that some phenotypes are enhanced on a mixed background while others are suppressed. 相似文献
12.
Sun H Satake W Zhang C Nagai Y Tian Y Fu S Yu J Qian Y Qian Y Chu J Toda T 《Journal of human genetics》2011,56(4):330-334
Parkinson's disease is a degenerative central nervous system disorder that often impairs motor skills, speech and other functions. We discovered a large Chinese family showing primarily parkinsonism symptoms with autosomal dominant inheritance. Six affected individuals in the family showed typical parkinsonism symptoms, including pill-rolling tremor. Two other affected individuals showed cerebellar ataxia symptoms. A whole-genome scan using the 50K single nucleotide polymorphism array with three different linkage methods detected two positive regions on chromosome 12q24.1 and 5q13.3. The ATXN2 gene, responsible for spinocerebellar ataxia type 2 (SCA2) was located precisely in the center of the positive region on chromosome 12. Further analysis of SCA2 revealed heterozygous pathological CAG expansions in the family. The affected individuals' symptoms were typical of parkinsonism, but complex. Inverse correlation between CAG repeat size and age of onset is not obvious in this pedigree. This parkinsonism-predominant SCA2 family shared the same disease gene locus with other 'standard' SCA2 families, but it is possible that variations in one or more modifier genes might account for the parkinsonism-predominant SCA2 predisposition observed in this pedigree. 相似文献
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16.
Cloning and expression of a lymphocyte activation gene (LAG-1) 总被引:1,自引:0,他引:1
E Baixeras S Roman-Roman S Jitsukawa C Genevee S Mechiche E Viegas-Pequignot T Hercend F Triebel 《Molecular immunology》1990,27(11):1091-1102
Using subtractive hybridization of a cDNA library we have identified a human gene, termed LAG-1 (for "Lymphocyte Activation Gene-1"). This cDNA codes for a 69 amino-acid polypeptide which belongs to a new class of recently described proteins secreted by activated lymphocytes and/or monocytes. The LAG-1 gene was cloned, sequenced and its chromosomal location assigned to chromosome 17 (q21 band). The promoter region of the LAG-1 gene was shown to include a GM-CSF-like decanucleotide sequence. Using a baculovirus vector expression system, we found that a 10 kDa recombinant LAG-1 protein is secreted by AcNPV infected SF9 cells, as determined in Western blot experiments by the reactivity of specific anti-peptidic heteroantibodies. Finally the natural LAG-1 protein was precipitated from the supernatant of internally labeled activated Nk cells and shown to migrate as a single entity of 14 kDa in SDS-PAGE analysis. 相似文献
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18.
Chemiluminescent detection of blotted PCR products (CB-PCR) of two CAG dynamic mutations (Huntington''s disease and spinocerebellar ataxia type 1). 总被引:1,自引:0,他引:1
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S Castellví-Bel T Matilla M I Banchs H Kruyer J Corral M Milà X Estivill 《Journal of medical genetics》1994,31(8):654-655
We have used a non-isotopic PCR assay based on the chemiluminescent detection of blotted PCR products (CB-PCR) for two dynamic mutation diseases (Huntington's disease and spinocerebellar ataxia type 1). This gives an accurate sizing of alleles and permits a rapid analysis of at risk persons. The system involves PCR of the samples, separation of alleles on polyacrylamide gels, Southern blotting, and hybridisation with specific primers 3' labelled with fluorescein (F1)-dUTP as probes. CB-PCR retains the isotopic sensitivity for accurate allele determination, avoids isotopic manipulation, and provides the advantages of safety, long term storage of probes, and recycling of hybridisation solutions. 相似文献
19.
Obayashi M Ishikawa K Izumi Y Takahashi M Niimi Y Sato N Onodera O Kaji R Nishizawa M Mizusawa H 《Journal of human genetics》2012,57(3):202-206
Spinocerebellar ataxia type 15 (SCA15) is an autosomal dominant neurodegenerative disorder clinically characterized by late-onset, slowly progressive pure cerebellar ataxia. This disease is caused by a heterozygous deletion of the inositol 1, 4, 5-triphosphate receptor type 1 (ITPR1) gene, suggesting that haploinsufficiency of the receptor function is the plausible disease mechanism. To clarify the prevalence of SCA15 in Japan, we designed four sets of probes and primers in different regions of ITPR1 and performed TaqMan PCR assay to search for gene deletions in 226 index SCA patients excluded for repeat expansion disorders. Deletion was found in only one patient, in whom gait ataxia started at 51 years of age and progressed to show cerebellar ataxia. This study demonstrates a simple but efficient method for screening ITPR1 deletion. We also conclude that ITPR1 gene deletions are much rare in Japan than in Europe, comprising only 0.3% in all SCAs in Japan. 相似文献
20.
Iwaki A Kawano Y Miura S Shibata H Matsuse D Li W Furuya H Ohyagi Y Taniwaki T Kira J Fukumaki Y 《Journal of medical genetics》2008,45(1):32-35
We have previously mapped autosomal dominant spinocerebellar ataxia (SCA) 16 to 3p26, overlapping with the locus of SCA15. Recently, partial deletions of ITPR1 and the neighbouring SUMF1 in the SCA15 and two additional families were reported. In the present study we determined the copy number of these genes by real time quantitative polymerase chain reaction (PCR) and found a heterozygous deletion of exons 1-48 of ITPR1, but not SUMF1 in SCA16. Breakpoint analysis revealed that the size of the deletion is 313,318 bp and the telomeric breakpoint is located in the middle of their intergenic region. Our data provide evidence that haploinsufficiency of ITPR1 alone causes SCA16 and SCA15. 相似文献