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1.
A Third Locus for Autosomal Dominant Cerebellar Ataxia Type 1 Maps to Chromosome 14q24.3-qter: Evidence for the Existence of a Fourth Locus
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Giovanni Stevanin Eric Le Guern Nicole Ravis Herv Chneiweiss Alexandra Dürr Graldine Cancel Alain Vignal Anne-Laure Boch Merle Ruberg Christiane Penet Yolaine Pothin Isabelle Lagroua Michel Haguenau Grald Rancurel Jean Weissenbach Yves Agid Alexis Brice 《American journal of human genetics》1994,54(1):11-20
The autosomal dominant cerebellar ataxias (ADCA) type I are a group of neurological disorders that are clinically and genetically heterogeneous. Two genes implicated in the disease, SCA1 (spinal cerebellar ataxia 1) and SCA2, are already localized. We have mapped a third locus to chromosome 14q24.3-qter, by linkage analysis in a non-SCA1/non-SCA2 family and have confirmed its existence in a second such family. We suggest designating this new locus “SCA3.” Combined analysis of the two families restricted the SCA3 locus to a 15-cM interval between markers D14S67 and D14S81. The gene for Machado-Joseph disease (MJD), a clinically different form of ADCA type I, has been recently assigned to chromosome 14q24.3-q32. Although the SCA3 locus is within the MJD region, linkage analyses cannot yet demonstrate whether they result from mutations of the same gene. Linkage to all three loci (SCA1, SCA2, and SCA3) was excluded in another family, which indicates the existence of a fourth ADCA type I locus. 相似文献
2.
Mutation detection in Machado-Joseph disease using repeat expansion detection. 总被引:3,自引:0,他引:3
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K. Lindblad A. Lunkes P. Maciel G. Stevanin C. Zander T. Klockgether T. Ratzlaff A. Brice G. A. Rouleau T. Hudson G. Auburger M. Schalling 《Molecular medicine (Cambridge, Mass.)》1996,2(1):77-85
BACKGROUND: Several neurological disorders have recently been explained through the discovery of expanded DNA repeat sequences. Among these is Machado-Joseph disease, one of the most common spinocerebellar ataxias (MJD/SCA3), caused by a CAG repeat expansion on chromosome 14. A useful way of detecting repeat sequence mutations is offered by the repeat expansion detection method (RED), in which a thermostable ligase is used to detect repeat expansions directly from genomic DNA. We have used RED to detect CAG expansions in families with either MJD/SCA3 or with previously uncharacterized spinocerebellar ataxia (SCA). MATERIALS AND METHODS: Five MJD/SCA3 families and one SCA family where linkage to SCA1-5 had been excluded were analyzed by RED and polymerase chain reaction (PCR). RESULTS: An expansion represented by RED products of 180-270 bp segregated with MJD/SCA3 (p < 0.00001) in five families (n = 60) and PCR products corresponding to 66-80 repeat copies were observed in all affected individuals. We also detected a 210-bp RED product segregating with disease (p < 0.01) in a non-SCA1-5 family (n = 16), suggesting involvement of a CAG expansion in the pathophysiology. PCR analysis subsequently revealed an elongated MJD/SCA3 allele in all affected family members. CONCLUSIONS: RED products detected in Machado-Joseph disease families correlated with elongated PCR products at the MJD/SCA3 locus. We demonstrate the added usefulness of RED in detecting repeat expansions in disorders where linkage is complicated by phenotyping problems in gradually developing adult-onset disorders, as in the non-SCA1-5 family examined. The RED method is informative without any knowledge of flanking sequences. This is particularly useful when studying diseases where the mutated gene is unknown. We conclude that RED is a reliable method for analyzing expanded repeat sequences in the genome. 相似文献
3.
D H Geschwind S Perlman C P Figueroa L J Treiman S M Pulst 《American journal of human genetics》1997,60(4):842-850
The dominant cerebellar ataxias (ADCAs) represent a clinically and genetically heterogeneous group of disorders linked by progressive deterioration in balance and coordination. The utility of genetic classification of the ADCAs has been highlighted by the striking variability in clinical phenotype observed within families and the overlap in clinical phenotype observed between those with different genotypes. The recent demonstration that spinocerebellar ataxia type 2 (SCA2) is caused by a CAG repeat expansion within the ataxin-2 gene has allowed us to determine the frequency of SCA2 compared with SCA1, SCA3/Machado-Joseph disease (MJD), and dentatorubropallidoluysian atrophy (DRPLA) in patients with sporadic and inherited ataxia. SCA2 accounts for 13% of patients with ADCA (without retinal degeneration), intermediate between SCA1 and SCA3/MJD, which account for 6% and 23%, respectively. Together, SCA1, SCA2, and SCA3/MJD constitute >40% of the mutations leading to ADCA I in our population. No patient without a family history of ataxia, or with a pure cerebellar or spastic syndrome, tested positive for SCA1, SCA2, or SCA3. No overlap in ataxin-2 allele size between normal and disease chromosomes, or intermediate-sized alleles, were observed. Repeat length correlated inversely with age at onset, accounting for approximately 80% of the variability in onset age. Haplotype analysis provided no evidence for a single founder chromosome, and diverse ethnic origins were observed among SCA2 kindreds. In addition, a wide spectrum of clinical phenotypes was observed among SCA2 patients, including typical mild dominant ataxia, the MJD phenotype with facial fasciculations and lid retraction, and early-onset ataxia with a rapid course, chorea, and dementia. 相似文献
4.
Autosomal dominant cerebellar ataxia type III: linkage in a large British family to a 7.6-cM region on chromosome 15q14-21.3.
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P F Worth P Giunti C Gardner-Thorpe P H Dixon M B Davis N W Wood 《American journal of human genetics》1999,65(2):420-426
Autosomal dominant cerebellar ataxia type III (ADCA III) is a relatively benign, late-onset, slowly progressive neurological disorder characterized by an uncomplicated cerebellar syndrome. Three loci have been identified: a moderately expanded CAG trinucleotide repeat in the SCA 6 gene, the SCA 5 locus on chromosome 11, and a third locus on chromosome 22 (SCA 10). We have identified two British families in which affected individuals do not have the SCA 6 expansion and in which the disease is not linked to SCA 5 or SCA 10. Both families exhibit the typical phenotype of ADCA III. Using a genomewide searching strategy in one of these families, we have linked the disease phenotype to marker D15S1039. Construction of haplotypes has defined a 7.6-cM interval between the flanking markers D15S146 and D15S1016, thereby assigning another ADCA III locus to the proximal long-arm of chromosome 15 (SCA 11). We excluded linkage of the disease phenotype to this region in the second family. These results indicate the presence of two additional ADCA III loci and more clearly define the genetic heterogeneity of ADCA III. 相似文献
5.
Miguel Angel Pujana Monica Gratacós Jordi Corral Isabel Banchs Aurora Sánchez David Genís Carlos Cervera Víctor Volpini X. Estivill 《Human genetics》1997,101(1):18-21
Genetic anticipation – increasing severity and a decrease in the age of onset with successive generations of a pedigree –
is clearly present in autosomal dominant cerebellar ataxia (ADCA). Anticipation is correlated with expansion of the CAG/CTG
repeat sequence to sizes above those in the normal range through the generations of a pedigree. Genetic heterogeneity has
been demonstrated for ADCA, with four cloned genes (SCA1, SCA2, SCA3/MJD, and SCA6) and three mapped loci (SCA4, SCA5 and
SCA7). Another related dominant ataxia, dentatorubral-pallidoluysian atrophy (DRPLA), presents anticipation with CAG/CTG repeat
expansions. We had previously analysed ADCA patients who had not shown repeat expansions in cloned genes for CAG/CTG repeat
expansions by the repeat expansion detection method (RED) and had detected expansions of between 48 and 88 units in 17 unrelated
familial cases. We present here an analysis of 13 genes and expressed sequence tags (ESTs) containing 10 or more CAG/ CTG
repeat sequences selected from public databases in the 17 unrelated ADCA patients. Of the 13 selected genes and ESTs, 9 were
found to be polymorphic with heterozygosities ranging between 0.09 and 0.80 and 2 to 17 alleles. In ADCA patients none of
the loci showed expansions above the normal range of the CAG/CTG repeat sequences, excluding them as the mutation causing
ADCA.
Received: 28 May 1997 / Accepted: 30 June 1997 相似文献
6.
Spinocerebellar ataxia type 1 and Machado-Joseph disease: incidence of CAG expansions among adult-onset ataxia patients from 311 families with dominant, recessive, or sporadic ataxia. 总被引:6,自引:1,他引:5
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L P Ranum J K Lundgren L J Schut M J Ahrens S Perlman J Aita T D Bird C Gomez H T Orr 《American journal of human genetics》1995,57(3):603-608
The ataxias are a complex group of diseases with both environmental and genetic causes. Among the autosomal dominant forms of ataxia the genes for two, spinocerebellar ataxia type 1 (SCA1) and Machado-Joseph disease (MJD), have been isolated. In both of these disorders the molecular basis of disease is the expansion of an unstable CAG trinucleotide repeat. To assess the frequency of the SCA1 and MJD trinucleotide repeat expansions among individuals diagnosed with ataxia we have collected DNA from individuals representing 311 families with adult-onset ataxia of unknown etiology and screened these samples for trinucleotide repeat expansions within the SCA1 and MJD genes. Within this group there are 149 families with dominantly inherited ataxia. Of these, 3% had SCA1 trinucleotide repeat expansions, whereas 21% were positive for the MJD trinucleotide expansion. Thus, together SCA1 and MJD represent 24% of the autosomal dominant ataxias in our group, and the frequency of MJD is substantially greater than that of SCA1. For the 57 patients with MJD trinucleotide repeat expansions, a strong inverse correlation between CAG repeat size and age at onset was observed (r = -.838). Among the MJD patients, the normal and affected ranges of CAG repeat size are 14-40 and 68-82 repeats, respectively. For SCA1 the normal and affected ranges are much closer, containing 19-38 and 40-81 CAG repeats, respectively. 相似文献
7.
The autosomal dominant late onset spinocerebellar ataxias (SCAs) are genetically heterogeneous. Three genes, SCA1 on 6p,
SCA2 on 12q and MJD1 on 14q, have been isolated for SCA1, SCA2 and Machado-Joseph disease (MJD), respectively. In these three
autosomal dominant disorders the mutation is an expanded CAG repeat. Evidence for heterogeneity in families not linked to
the SCA1, SCA2 and MJD loci is provided by the mapping of SCA loci to chromosomes 16q, 11cen and 3p. A total of 14 South African
kindreds and 22 sporadic individuals with SCA were investigated for the expanded SCA1 and MJD repeats. None of the families
nor the sporadic individuals showed expansion of the MJD repeat. Expanded SCA1 and CAG repeats were found to cosegregate with
the disorder in six of the families tested and were also observed in one sporadic individual with a negative family history
of SCA. The use of the microsatellite markers D6S260, D6S89 and D6S274 provided evidence that the expanded SCA1 repeats segregated
with three distinct haplotypes in the six families. Use of the highly polymorphic tightly linked microsatellite markers is
still important as this stage, particularly where this coincides with the possibility of a homozygous genotype with the trinucleotide
repeat marker. Importantly, our molecular findings indicate: (1) an absence of MJD expanded repeats underlying SCA; (2) the
major disease in this group is due to mutations in the SCA1 gene; and (3) the familial disorder in the majority population
group (i.e. mixed ancestry) in the Western Cape region of South Africa is most likely to be the result of two distinct founder
events.
Received: 4 November 1996 / Accepted: 6 February 1997 相似文献
8.
Saleem Q Choudhry S Mukerji M Bashyam L Padma MV Chakravarthy A Maheshwari MC Jain S Brahmachari SK 《Human genetics》2000,106(2):179-187
Expansion of CTG/CAG trinucleotide repeats has been shown to cause a number of autosomal dominant cerebellar ataxias (ADCA) such as SCA1, SCA2, SCA3/ MJD, SCA6, SCA7, SCA8 and DRPLA. There is a wide variation in the clinical phenotype and prevalence of these ataxias in different populations. An analysis of ataxias in 42 Indian families indicates that SCA2 is the most frequent amongst all the ADCAs we have studied. In the SCA2 families, together with an intergenerational increase in repeat size, a horizontal increase with the birth order of the offspring was also observed, indicating an important role for parental age in repeat instability. This was strengthened by the detection of a pair of dizygotic twins with expanded alleles showing the same repeat number. Haplotype analysis indicates the presence of a common founder chromosome for the expanded allele in the Indian population. Polymorphism of CAG repeats in 135 normal individuals at the SCA loci studied showed similarity to the Caucasian population but was significantly different from the Japanese population. 相似文献
9.
Mutational screening of the USH2A gene in Spanish USH patients reveals 23 novel pathogenic mutations
Gema Garcia-Garcia Maria J Aparisi Teresa Jaijo Regina Rodrigo Ana M Leon Almudena Avila-Fernandez Fiona Blanco-Kelly Sara Bernal Rafael Navarro Manuel Diaz-Llopis Montserrat Baiget Carmen Ayuso Jose M Millan Elena Aller 《Orphanet journal of rare diseases》2011,6(1):1-13
Type I autosomal dominant cerebellar ataxia (ADCA) is a type of spinocerebellar ataxia (SCA) characterized by ataxia with other neurological signs, including oculomotor disturbances, cognitive deficits, pyramidal and extrapyramidal dysfunction, bulbar, spinal and peripheral nervous system involvement. The global prevalence of this disease is not known. The most common type I ADCA is SCA3 followed by SCA2, SCA1, and SCA8, in descending order. Founder effects no doubt contribute to the variable prevalence between populations. Onset is usually in adulthood but cases of presentation in childhood have been reported. Clinical features vary depending on the SCA subtype but by definition include ataxia associated with other neurological manifestations. The clinical spectrum ranges from pure cerebellar signs to constellations including spinal cord and peripheral nerve disease, cognitive impairment, cerebellar or supranuclear ophthalmologic signs, psychiatric problems, and seizures. Cerebellar ataxia can affect virtually any body part causing movement abnormalities. Gait, truncal, and limb ataxia are often the most obvious cerebellar findings though nystagmus, saccadic abnormalities, and dysarthria are usually associated. To date, 21 subtypes have been identified: SCA1-SCA4, SCA8, SCA10, SCA12-SCA14, SCA15/16, SCA17-SCA23, SCA25, SCA27, SCA28 and dentatorubral pallidoluysian atrophy (DRPLA). Type I ADCA can be further divided based on the proposed pathogenetic mechanism into 3 subclasses: subclass 1 includes type I ADCA caused by CAG repeat expansions such as SCA1-SCA3, SCA17, and DRPLA, subclass 2 includes trinucleotide repeat expansions that fall outside of the protein-coding regions of the disease gene including SCA8, SCA10 and SCA12. Subclass 3 contains disorders caused by specific gene deletions, missense mutation, and nonsense mutation and includes SCA13, SCA14, SCA15/16, SCA27 and SCA28. Diagnosis is based on clinical history, physical examination, genetic molecular testing, and exclusion of other diseases. Differential diagnosis is broad and includes secondary ataxias caused by drug or toxic effects, nutritional deficiencies, endocrinopathies, infections and post-infection states, structural abnormalities, paraneoplastic conditions and certain neurodegenerative disorders. Given the autosomal dominant pattern of inheritance, genetic counseling is essential and best performed in specialized genetic clinics. There are currently no known effective treatments to modify disease progression. Care is therefore supportive. Occupational and physical therapy for gait dysfunction and speech therapy for dysarthria is essential. Prognosis is variable depending on the type of ADCA and even among kindreds. 相似文献
10.
The gene for autosomal dominant cerebellar ataxia type II is located in a 5-cM region in 3p12-p13: genetic and physical mapping of the SCA7 locus. 总被引:4,自引:1,他引:3
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G. David P. Giunti N. Abbas P. Coullin G. Stevanin W. Horta R. Gemmill J. Weissenbach N. Wood S. Cunha H. Drabkin A. E. Harding Y. Agid A. Brice 《American journal of human genetics》1996,59(6):1328-1336
Two families with autosomal dominant cerebellar ataxia with pigmentary macular dystrophy (ADCA type II) were investigated. Analysis of 23 parent-child couples demonstrated the existence of marked anticipation, greater in paternal than in maternal transmissions, with earlier age at onset and a more rapid clinical course in successive generations. Clinical analysis revealed the presence of a great variability in age at onset, initial symptom, and associated signs, confirming the characteristic clinical heterogeneity of ADCA type II. The gene for ADCA type II previously was mapped to the spinocerebellar ataxia 7 (SCA7) locus on chromosome 3p12-p21.1. Linkage analysis of the two new families of different geographic origin confirmed the characteristic genetic homogeneity of ADCA type II, distinguishing it from ADCA type I. Haplotype analysis permitted refinement of the SCA7 region to the 5-cM interval between markers D3S1312 and D3S1600 on chromosome 3p12-p13. Eighteen sequence-tagged sites were used for the construction of an integrated map of the candidate region, based on a YACs contig. The entire candidate region is contained in a single nonchimeric YAC of 660 kb. The probable involvement of a CAG trinucleotide expansion, suggested by previous studies, should greatly facilitate the identification of the gene for ADCA type II. 相似文献
11.
Miguel Angel Pujana Jordi Corral Mònica Gratacòs Onofre Combarros José Berciano David Genís Isabel Banchs Xavier Estivill Víctor Volpini 《Human genetics》1999,104(6):516-522
Autosomal dominant cerebellar ataxias (ADCA) are a clinically heterogeneous group of neurodegenerative disorders caused by
unstable CAG repeat expansions encoding polyglutamine tracts. Five spinocerebellar ataxia genes (SCA1, SCA2, SCA3, SCA6 and SCA7) and another related dominant ataxia gene (DRPLA) have been cloned, allowing the genetic classification of these disorders. We present here the molecular analysis of 87 unrelated
familial and 60 sporadic Spanish cases of spinocerebellar ataxia. For ADCA cases 15% were SCA2, 15% SCA3, 6% SCA1, 3% SCA7, 1% SCA6 and 1% DRPLA, an extremely rare mutation in Caucasoid populations. About 58% of ADCA cases remained genetically unclassified. All the
SCA1 cases belong to the same geographical area and share a common haplotype for the SCA1 mutation. The expanded alleles ranged from 41 to 59 repeats for SCA1, 17 to 29 for SCA2, 67 to 77 for SCA3, and 38 to 113 for SCA7. One SCA6 case had 25 repeats and one DRPLA case had 63 repeats. The highest CAG repeat variation in meiotic transmission of expanded alleles was detected in SCA7, this being of +67 units in one paternal transmission and giving rise to a 113 CAG repeat allele in a patient who died at
3 years of age. Meiotic transmissions have also shown a tendency to more frequent paternal transmission of expanded alleles
in SCA1 and maternal in SCA7. All SCA1 and SCA2 expanded alleles analyzed consisted of pure CAG repeats, whereas normal alleles were interrupted by 1–2 CAT trinucleotides
in SCA1, except for three alleles of 6, 14 and 21 CAG repeats, and by 1–3 CAA trinucleotides in SCA2. No SCA or DRPLA mutations were detected in the 60 sporadic cases of spinocerebellar ataxia, but one late onset patient was
identified as a recessive form due to GAA-repeat expansions in the Friedreich’s ataxia gene.
Received: 6 January 1999 / Accepted: 18 March 1999 相似文献
12.
脊髓小脑性共济失调3型(SCA3/MJD),是一种因致病基因MJD1编码区内CAG异常重复扩增所致的常染色体显性遗传迟发性神经退行性疾病. 已知PINK1蛋白可通过抗氧化稳定线粒体,阻止帕金森疾病的发生,但其在SCA3/MJD中的作用尚不清楚. 本文旨在探索过表达PINK1对SCA3/MJD转基因果蝇模型的保护作用.本研究利用Mhc-Gal4启动子表达致病蛋白质片段(MJDtr-Q78)获得SCA3/MJD果蝇模型,分别运用过表达PINK1和RNA干扰PINK1研究其在SCA3/MJD果蝇模型中的功能.结果显示,疾病模型组翅膀异常率增高,线粒体呈过度融合状态,ATP值降低;PINK1 RNA干扰组翅膀异常率明显增高,线粒体呈显著过度融合状态,ATP值明显降低;PINK1过表达组翅膀异常率明显降低,线粒体清晰、完整,ATP值明显升高.本文的结果提示, 过表达PINK1对SCA3/MJD转基因果蝇模型起保护作用,而RNA干扰PINK1表达加重SCA3/MJD转基因果蝇模型病情.PINK1在SCA3/MJD果蝇模型中的功能可能通过改善细胞内线粒体功能实现. 相似文献
13.
The Machado-Joseph disease locus is different from the spinocerebellar ataxia locus (SCA1). 总被引:5,自引:0,他引:5
W J Carson J Radvany L A Farrer D Vincent R N Rosenberg P M MacLeod G A Rouleau 《Genomics》1992,13(3):852-855
Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative spinocerebellar ataxia that has been described primarily in families of Azorean or Portuguese descent. MJD and chromosome 6p-linked spinocerebellar ataxia (SCA1) are difficult to differentiate clinically, and it has been suggested that they may be allelic variants of the same disorder. We have tested MJD families for linkage to six DNA sequence polymorphisms located on chromosome 6p, including the highly informative dinucleotide repeat, D6S89. Seventeen centimorgans telomeric to and 41 cM centromeric to D6S89, a region that includes the SCA1 locus reported to be within 3 cM of D6S89, have been excluded. These data provide conclusive evidence that MJD and SCA1 are nonallelic. 相似文献
14.
Molecular and clinical study of 18 families with ADCA type II: evidence for genetic heterogeneity and de novo mutation.
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P Giunti G Stevanin P F Worth G David A Brice N W Wood 《American journal of human genetics》1999,64(6):1594-1603
The SCA7 mutation has been found in 54 patients and 7 at-risk subjects from 17 families who have autosomal dominant cerebellar ataxia (ADCA) II with progressive pigmentary maculopathy. In one isolated case, haplotype reconstruction through three generations confirmed a de novo mutation owing to paternal meiotic instability. Different disease-associated haplotypes segregated among the SCA7-positive kindreds, which indicated a multiple origin of the mutation. One family with the clinical phenotype of ADCA type II did not have the CAG expansion that indicated locus heterogeneity. The distribution of the repeat size in 944 independent normal chromosomes from controls, unaffected at-risk subjects, and one affected individual fell into two ranges. The majority of the alleles were in the first range of 7-19 CAG repeats. A second range could be identified with 28-35 repeats, and we provide evidence that these repeats represent intermediate alleles that are prone to further expansion. The repeat size of the pathological allele, the widest reported for all CAG-repeat disorders, ranged from 37 to approximately 220. The repeat size showed significant negative correlation with both age at onset and age at death. Analysis of the clinical features in the patients with SCA7 confirmed that the most frequently associated features are pigmentary maculopathy, pyramidal tract involvement, and slow saccades. The subjects with <49 repeats tended to have a less complicated neurological phenotype and a longer disease duration, whereas the converse applied to subjects with >/=49 repeats. The degree of instability during meiotic transmission was greater than in all other CAG-repeat disorders and was particularly striking in paternal transmission, in which a median increase in repeat size of 6 and an interquartile range of 12 were observed, versus a median increase of 3 and interquartile range of 3.5 in maternal transmission. 相似文献
15.
Machado-Joseph disease or spinocerebellar ataxia 3 (SCA3) is a progressive neurodegenerative disorder caused by pathological expansion of a trinucleotide repeat motif present within exon 4 of the MJD1 gene. Previous attempts to create a transgenic animal model have failed to produce a neurological deficit truly representative of the disease phenotype. This appears to be the result of inappropriate expression of the mutant protein in neuronal populations generally spared in the disease state. Introduction of a human disease gene in the context of a yeast artificial chromosome clone containing endogenous regulatory elements would enhance the potential for correct tissue/cell-specific expression at physiological levels. We report the introduction of expanded CAG repeat motifs into a 250kb yeast artificial chromosome clone spanning the MJD1 locus using two rounds of homologous recombination. Transformants exhibited both expansions and contractions of the motif with alleles ranging in size from 48 to 84 repeat units. The availability of these clones for modelling of the disease in transgenic animals should allow elucidation of the role of repeat length in the phenotypic spectrum of the disease. 相似文献
16.
脊髓小脑共济失调第7型的临床特征及基因突变研究 总被引:1,自引:0,他引:1
对一脊髓小脑性共济失调(Spinocerebellar ataxia, SCA)家系的患者进行临床特征及相关基因突变研究。对该家系进行详细的病史采集, 并对患者行视力、眼底血管造影、眼底拍照、视觉诱发电位、视网膜电图以及头颅MRI等辅助检查; 采用聚合酶链反应分别扩增SCA1、SCA2、SCA3、SCA6、SCA7、SCA17及DRPLA基因的CAG重复序列, 用8%变性聚丙烯酰胺凝胶电泳及直接测序进行突变分析。结果2名患者主要表现为小脑性共济失调、视力下降、眼底视网膜色素变性、小脑和脑干萎缩; 并存在SCA7基因的突变, 而未发现SCA1、SCA2、SCA3、SCA6、SCA17及DRPLA基因突变。说明该家系为SCA7突变家系, SCA7基因中CAG三核苷酸重复拷贝数的异常扩增是其致病原因。 相似文献
17.
Mingli Hsieh Hui-Fang Tsai Tsong-Ming Lu Chien-Ying Yang Hung-Ming Wu S.-Y. Li 《Human genetics》1997,100(2):155-162
Machado-Joseph disease (MJD) is an autosomal dominant spinocerebellar degeneration characterized by cerebellar ataxia and
pyramidal signs associated in varying degrees with a dystonic-rigid extrapyramidal syndrome or peripheral amyotrophy. Unstable
CAG trinucleotide repeat expansion in the MJD gene on the long arm of chromosome 14 has been identified as the pathological
mutation for MJD. While investigating the distribution of CAG repeat lengths of the MJD gene in Taiwan’s population, we have
identified 18 MJD-affected patients and 12 at-risk individuals in seven families. In addition, we have analyzed the range
of CAG repeat lengths in 96 control individuals. The CAG repeat number ranged from 13 to 44 in the controls and 72–85 in the
affected and at- risk individuals. Our results indicated that the CAG repeat number was inversely correlated with the age
of onset. The differences in CAG repeat length between parent and child and between siblings are greater with paternal transmission
than maternal transmission. Our data show a tendency towards the phenomenon of anticipation in the MJD families but do not
support unidirectional expansion of CAG repeats during transmission. We also demonstrated that PCR amplification of the CAG
repeats in the MJD gene from villous DNA was possible and might prove useful as a diagnostic tool for affected families in
the future.
Received: 4 December 1996 / Accepted: 5 March 1997 相似文献
18.
Elspeth C. Twist Lindsay A. Farrer Patrick M. Macleod Joao Radvany Susan Chamberlain Roger N. Rosenberg Guy A. Rouleau 《Human genetics》1994,93(3):335-338
Machado Joseph disease (MJD) is a progressive, spinocerebellar ataxia (SCA) with an autosomal dominant mode of inheritance and almost complete penetrance. Clinically, it is difficult to distinguish it from other autosomal dominantly inherited ataxias, and it has been suggested that MJD may be caused by an allelic variant of SCA. Exclusion of MJD from the SCA1 locus on chromosome 6p has previously been demonstrated. However, following the recent assignment of a second locus for spinocerebellar ataxia (SCA2) to chromosome 12q in a large Cuban kindred of Spanish origin, we have investigated linkage in MJD families using the two markers, D12S58 and PLA2, that flank this disease gene. The MJD locus was definitively excluded from an interval spanning approximately 70 cM, which includes these loci. These studies demonstrate that MJD and SCA2 are genetically distinct despite similarities in disease phenotype and ancestral origins of the patients. Thus, the as yet unmapped MJD locus represents a third SCA locus, providing further evidence for genetic heterogeneity within these disorders. 相似文献
19.
为探讨广西地区脊髓小脑性共济失调(Spinocerebellar ataxia, SCA)患者各种亚型类型特点及分布状况, 应用聚合酶链反应(Polymerase chain reaction, PCR)、毛细管电泳(Capillary electrophoresis, CE)片段分析等技术检测分析遗传性共济失调患者的SCA1、SCA2、SCA3/MJD、SCA6、SCA7和SCA12 (CAG)n突变。在6个SCA家系共检出21例患者和19例症状前患者均为SCA3/MJD突变, CAG重复数分别为59~70次和60~73次。未检测到SCA1、SCA2、SCA6、SCA7和SCA12(CAG)n突变。研究表明, 广西地区的SCA病人主要为SCA3/MJD型, 患者的CAG重复数低于过去的报道。 相似文献
20.
R. Matsumura Tetsuya Takayanagi Kayoko Murata Naonobu Futamura Makito Hirano Satoshi Ueno 《Human genetics》1996,98(6):643-645
The mutation responsible for Machado-Joseph disease (MJD) has been identified as an expansion of a CAG trinucleotide repeat
in a novel gene on chromosome 14q32.1. The CAG repeat tract is followed by C or G, and alleles are thereby divided into two
types on the basis of molecular configuration, (CAG)nC and (CAG)nG. We have studied the relationship between the repeat length
and the configuration in 38 patients from 28 Japanese families with MJD, and 31 unrelated normal Japanese subjects. The CAG
repeat length in 100 normal alleles ranged from 13 to 37 repeats, while 38 MJD patients had one expanded allele with 64 to
84 repeats. Surprisingly, the expanded alleles had exclusively the (CAG)nC configuration, while both (CAG)nC and (CAG)nG were
seen in normal alleles from MJD and control subjects. Furthermore, in normal alleles, the CAG repeat tract was significantly
longer in (CAG)nC than in (CAG)nG. These findings suggest that the (CAG)nC configuration is related to repeat instability
of the MJD gene.
Received: 23 April 1996 / Revised: 24 June 1996 相似文献