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1.  Spinocerebellar ataxia type 17: Report of a family with reduced penetrance of an unstable Gln49 TBP allele, haplotype analysis supporting a founder effect for unstable alleles and comparative analysis of SCA17 genotypes 
BMC Medical Genetics  2005;6:27.
Background
Spinocerebellar ataxia type 17 (SCA17), a neurodegenerative disorder in man, is caused by an expanded polymorphic polyglutamine-encoding trinucleotide repeat in the gene for TATA-box binding protein (TBP), a main transcription factor. Observed pathogenic expansions ranged from 43 – 63 glutamine (Gln) codons (Gln43–63). Reduced penetrance is known for Gln43–48 alleles. In the vast majority of families with SCA17 an expanded CAG repeat interrupted by a CAA CAG CAA element is inherited stably.
Results
Here, we report the first pedigree with a Gln49 allele that is a) not interrupted, b) unstable upon transmission, and c) associated with reduced penetrance or very late age of onset. The 76-year-old father of two SCA17 patients carries the Gln49 TBP allele but presents without obvious neurological symptoms. His children with Gln53 and Gln52 developed ataxia at the age of 41 and 50. Haplotype analysis of this and a second family both with uninterrupted expanded and unstable pathological SCA17 alleles revealed a common core genotype not present in the interrupted expansion of an unrelated SCA17 patient. Review of the literature did not present instability in SCA17 families with expanded alleles interrupted by the CAA CAG CAA element.
Conclusion
The presence of a Gln49 SCA17 allele in an asymptomatic 76-year-old male reams the discussion of reduced penetrance and genotypes producing very late disease onset. In SCA17, uninterrupted expanded alleles of TBP are associated with repeat instability and a common founder haplotype. This suggests for uninterrupted expanded alleles a mutation mechanism and some clinical genetic features distinct from those alleles interrupted by a CAA CAG CAA element.
doi:10.1186/1471-2350-6-27
PMCID: PMC1177950  PMID: 15989694
2.  Psychotic-affective symptoms and multiple system atrophy expand phenotypes of spinocerebellar ataxia type 2 
BMJ Case Reports  2012;2012:bcr1020115061.
Spinocerebellar ataxia type 2 (SCA2) is a progressive neurodegenerative disorder, characterised by ataxic gait, slow saccades and peripheral neuropathy. Levodopa-responsive parkinsonism could be a clinical phenotype of SCA2, especially those of Chinese origin. In addition to these motor symptoms, SCA2 has been associated with depression and cognitive dysfunction, with only rare reports of psychosis. The authors report the presence of severe psychosis, major depression and multiple system atrophy in affected subjects of a Taiwanese family with intermediate CAG repeats within the ATXN2 gene. The identification of this rare and distinctive SCA2 phenotype expands the current knowledge of the phenotypic variability of SCA2 and suggests that modifier genes could influence the clinical phenotype of SCA2.
doi:10.1136/bcr.10.2011.5061
PMCID: PMC3316827  PMID: 22605703
3.  Clinical and Genetic Analysis of Spinocerebellar Ataxia in Mali 
Autosomal dominant cerebellar ataxia, currently denominated Spinocerebellar ataxia (SCAs) represents a heterogeneous group of neurodegenerative disorders affecting the cerebellum and its connections. We describe clinical and molecular findings in sixteen patients originating from Malian families, who suffer from progressive cerebellar ataxia syndrome. Molecular analysis allows genetic profiles of spinocerebellar ataxia to be distinguished. In seven patients, SCA type 2 (CAG) mutation was expanded from 39 to 43 repeats. SCA type 7(CAG)mutation was confirmed in six patients .Mutations were expanded from 49 to 59 repeats. In three patients, SCA type 3 was diagnosed and CAG mutation was expanded to 73 repeats.
Conclusions
Our data suggests that the most frequent types of SCA are SCA2 and SCA7. However, further studies are needed to confirm these preliminary results.
doi:10.1111/j.1468-1331.2011.03376.x
PMCID: PMC3136651  PMID: 21418439
Spinocerebellar ataxia- genetic; inherited disorders- Malians
4.  Spinocerebellar ataxia type 6 and episodic ataxia type 2 in a Korean family. 
Journal of Korean Medical Science  2001;16(6):809-813.
Spinocerebellar ataxia type 6 (SCA6), episodic ataxia type 2 (EA2) and familial hemiplegic migraine (FHM) have been known as allelic disorders, which are caused by the alteration of the alpha1A voltage-dependent calcium channel subunit. Expansions of the CAG repeat in the CACNA1A gene on the short arm of the chromosome 19 induce SCA6, and point mutations in the same gene are responsible for EA2 and FHM. In recent studies, both SCA6 and EA2 have been concurrently found in families with 26 CAG repeats without previously reported point mutations either in coding sequences or in intron-exon junctions. We describe a Korean family with CAG26 repeats in the CACNA1A gene. Some of the affected family members had progressive ataxia typical of SCA6 whereas others had episodic vertigo responsive to acetazolamide typical of EA2. Our family support that SCA6 and EA2 are allelic disorders with a high phenotypic variability.
PMCID: PMC3054805  PMID: 11748369
5.  Spinocerebellar ataxia type 6: genotype and phenotype in German kindreds 
OBJECTIVE—Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant cerebellar ataxia (ADCA) of which the mutation causing the disease has recently been characterised as an expanded CAG trinucleotide repeat in the gene coding for the α1A-subunit of the voltage dependent calcium channel. The aim was to further characterise the SCA6 phenotype
METHODS—The SCA6 mutation was investigated in 69 German families with ADCA and 61 patients with idiopathic sporadic cerebellar ataxia and the CAG repeat length of the expanded allele was correlated with the disease phenotype.
RESULTS—Expanded alleles were found in nine of 69 families as well as in four patients with sporadic disease. Disease onset ranged from 30 to 71 years of age and was significantly later than in other forms of ADCA. Age at onset correlated inversely with repeat length. The SCA6 phenotype comprises predominantly cerebellar signs in concordance with isolated cerebellar atrophy on MRI. Non-cerebellar systems were only mildly affected with external ophthalmoplegia, spasticity, peripheral neuropathy, and parkinsonism. Neither these clinical signs nor progression rate correlated with CAG repeat length.
CONCLUSIONS—This study provides the first detailed characterisation of the SCA6 phenotype. Clinical features apart from cerebellar signs were highly variable in patients with SCA6. By comparison with SCA1, SCA2, and SCA3 no clinical or electrophysiological finding was specific for SCA6. Therefore, the molecular defect cannot be predicted from clinical investigations. In Germany, SCA6 accounts for about 13% of families with ADCA. However, up to 30% of SCA6 kindreds may be misdiagnosed clinically as sporadic disease due to late manifestation in apparently healthy parents. Genetic testing is therefore recommended for the SCA6 mutation also in patients with putative sporadic ataxia.


PMCID: PMC2169927  PMID: 9436730
6.  Loss of Intrinsic Organization of Cerebellar Networks in Spinocerebellar Ataxia Type 1: Correlates with Disease Severity and Duration 
Cerebellum (London, England)  2011;10(2):218-232.
The spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of cerebellar degenerative disorders, characterized by progressive gait unsteadiness, hand incoordination, and dysarthria. The mutational mechanism in SCA1, a dominantly inherited form of SCA, consists of an expanded trinucleotide CAG repeat. In SCA1, there is loss of Purkinje cells, neuronal loss in dentate nucleus, olives, and pontine nuclei. In the present study, we sought to apply intrinsic functional connectivity analysis combined with diffusion tensor imaging to define the state of cerebellar connectivity in SCA1. Our results on the intrinsic functional connectivity in lateral cerebellum and thalamus showed progressive organizational changes in SCA1 noted as a progressive increase in the absolute value of the correlation coefficients. In the lateral cerebellum, the anatomical organization of functional clusters seen as parasagittal bands in controls is lost, changing to a patchy appearance in SCA1. Lastly, only fractional anisotropy in the superior peduncle and changes in functional organization in thalamus showed a linear dependence to duration and severity of disease. The present pilot work represents an initial effort describing connectivity biomarkers of disease progression in SCA1. The functional changes detected with intrinsic functional analysis and diffusion tensor imaging suggest that disease progression can be analyzed as a disconnection syndrome.
doi:10.1007/s12311-010-0214-5
PMCID: PMC3091958  PMID: 20886327
Networks; MRI; Biomarkers; Ataxia
7.  Spinocerebellar ataxia type 2 is associated with Parkinsonism and Lewy body pathology 
BMJ Case Reports  2011;2011:bcr0120113685.
Clinical phenotype of individuals with spinocerebellar ataxia 2 (SCA2) is characterised by cerebellar ataxia and cognitive impairment. Although L-dopa-responsive Parkinsonism is considered as a rare clinical presentation in SCA2, it has been brought to the attention of many neurologists in several studies. The authors report an autopsy case of SCA2 with Parkinsonism from a Japanese family using archival materials of our Brain Bank to describe unique neuropathologic findings. The individual clinically showed Parkinsonism as a predominant phenotype instead of cerebellar ataxia. Besides the classic SCA2 neuropathologic alterations, Lewy bodies and Lewy neurites were present in the brainstem nuclei. Genetic analysis revealed shorter abnormal expansion of CAG repeats (less than 39). In contrast, the authors could not find α-synuclein pathology in two SCA2 cases without Parkinsonism. The present case will provide a neuropathologic evidence of correlation between α-synucleinopathy and Parkinsonism of SCA2 as well as shed light on understanding the pathomechanism of Parkinsonism in SCA2.
doi:10.1136/bcr.01.2011.3685
PMCID: PMC3079476  PMID: 22700602
8.  Cell biology of spinocerebellar ataxia 
The Journal of Cell Biology  2012;197(2):167-177.
Ataxia is a neurological disorder characterized by loss of control of body movements. Spinocerebellar ataxia (SCA), previously known as autosomal dominant cerebellar ataxia, is a biologically robust group of close to 30 progressive neurodegenerative diseases. Six SCAs, including the more prevalent SCA1, SCA2, SCA3, and SCA6 along with SCA7 and SCA17 are caused by expansion of a CAG repeat that encodes a polyglutamine tract in the affected protein. How the mutated proteins in these polyglutamine SCAs cause disease is highly debated. Recent work suggests that the mutated protein contributes to pathogenesis within the context of its “normal” cellular function. Thus, understanding the cellular function of these proteins could aid in the development of therapeutics.
doi:10.1083/jcb.201105092
PMCID: PMC3328388  PMID: 22508507
9.  Uncloned expanded CAG/CTG repeat sequences in autosomal dominant cerebellar ataxia (ADCA) detected by the repeat expansion detection (RED) method. 
Journal of Medical Genetics  1998;35(2):99-102.
In some neurodegenerative diseases, genetic anticipation correlates with expansions of the CAG/CTG repeat sequence above the normal range through the generations of a pedigree. Among these neurodegenerative diseases are late onset autosomal dominant cerebellar ataxias (ADCA). ADCA are genetically heterogeneous disorders with different cloned genes for spinocerebellar ataxia type 1 (SCA1), type 2 (SCA2), type 3 or Machado-Joseph disease (SCA3/MJD), and type 6 (SCA6). Another related dominant ataxia, dentatorubral-pallidoluysian atrophy (DRPLA), also shows CAG/CTG repeat expansions. Genetic anticipation has been reported for all of them except for the recently cloned SCA6 gene. Other, as yet undetected SCA genes may show the same features. We have used the repeat expansion detection (RED) method to detect repeat expansions directly in DNA samples from ADCA patients not resulting from known genes. Our sample consists of 19 affected index cases, corresponding to 52.8% of our ADCA families without CAG/CTG repeat expansions in the SCA1, SCA2, SCA3/MJD, SCA6, or DRPLA genes. Eighty-nine percent of the index cases had expansions of a CAG/CTG sequence greater than 40 repeats by RED, while these were observed in only 26.9% of 78 healthy subjects from the general population (p < 0.0001). The distribution of RED fragments in controls and ADCA patients also shows significant differences with the Mann-Whitney U test (U = 376.5, p = 0.0007). Moreover, there was a significant inverse correlation between the size of expansion and the age of onset (r = -0.54, p = 0.018). These results show CAG/CTG repeat expansions of over 40 repeats in our sample of ADCA families not resulting from known SCA genes.
Images
PMCID: PMC1051211  PMID: 9507387
10.  ETS1 regulates the expression of ATXN2 
Human Molecular Genetics  2012;21(23):5048-5065.
Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant disorder caused by the expansion of a CAG tract in the ATXN2 gene. The SCA2 phenotype is characterized by cerebellar ataxia, neuropathy and slow saccades. SCA2 foreshortens life span and is currently without symptomatic or disease-modifying treatments. Identifying function-specific therapeutics for SCA2 is problematic due to the limited knowledge of ATXN2 function. As SCA2 is likely caused by a gain-of-toxic or gain-of-normal function like other polyglutamine disorders, targeting ATXN2 expression may represent a valid therapeutic approach. This study characterized aspects of ATXN2 expression control using an ATXN2 promoter-luciferase (luc) reporter construct. We verified the fidelity of construct expression by generating transgenic mice expressing the reporter construct. High reporter expression was seen in the cerebellum and olfactory bulb in vivo but there was relatively low expression in other tissues, similar to the expression of endogenous ataxin-2. We verified the second of two possible start codons as the functional start codon in ATXN2. By evaluating deletions in the ATXN2 promoter, we identified an E-twenty six (ETS)-binding site required for ATXN2 expression. We verified that endogenous ETS1 interacted with the ATXN2 promoter by an electromobility supershift assay and chromatin immunoprecipitation polymerase chain reaction. ETS1 overexpression increased ATXN2-luc (ATXN2-luciferase) as well as endogenous ATXN2 expression. Deletion of the putative ETS1-binding site abrogated the effects on the expression of ATXN2-luc. A dominant negative ETS1 and an ETS1 short-hairpin RNA both reduced ATXN2-luc expression. Our study broadens the understanding on the transcriptional control of ATXN2 and reveals specific regulatory features of the ATXN2 promoter that can be exploited therapeutically.
doi:10.1093/hmg/dds349
PMCID: PMC3490512  PMID: 22914732
11.  Analysis of spinocerebellar ataxia types 1, 2, 3, and 6, dentatorubral-pallidoluysian atrophy, and Friedreich's ataxia genes in spinocerebellar ataxia patients in the UK. 
Journal of Medical Genetics  1997;34(12):982-985.
Accurate clinical diagnosis of the spinocerebellar ataxias (SCAs) can be difficult because of overlap in phenotype with other disorders and variation in clinical manifestations. Six SCA loci have been mapped and four disease causing genes identified, in addition to the causative gene for Friedreich's ataxia (FA). All of the identified mutations are expansions of trinucleotide repeat tracts. The SCA2 and SCA6 genes were published recently. The extent of the normal CAG size ranges at these loci and the relative frequencies of the known causes of SCA in the UK are not known. This study first investigated the normal size ranges of the SCA2 and SCA6 loci by genotyping control populations of West African and South African subjects, since African populations generally show the greatest allelic diversity. We found one allele larger than the previously determined normal range for SCA2, and our results at the SCA6 locus agreed with the previously reported normal range. The second component of the study assessed the relative frequencies of the SCA1, 2, 3, and 6, DRPLA, and FA trinucleotide repeat mutations in 146 patients presenting with SCA-like symptoms referred to genetic diagnostic laboratories in the UK. We detected mutations in 14% of patients referred with a diagnosis of autosomal dominant SCA, and in 15% of patients referred with spinocerebellar ataxia where we did not have sufficient family history data available to allow categorisation as familial or sporadic cases. Friedreich's ataxia accounted for 3% of the latter category of cases in our sample, but the most common causes of SCA were SCA2 and SCA6.
PMCID: PMC1051147  PMID: 9429138
12.  Non-Ataxic Phenotypes of SCA8 Mimicking Amyotrophic Lateral Sclerosis and Parkinson Disease 
Background
Spinocerebellar ataxia (SCA) type 8 (SCA8) is an inherited neurodegenerative disorder caused by the expansion of untranslated CTA/CTG triplet repeats on 13q21. The phenomenology of SCA8 is relatively varied when compared to the other types of SCAs and its spectrum is not well established.
Case Report
Two newly detected cases of SCA8 with the nonataxic phenotype and unusual clinical manifestations such as dopaminergic-treatment-responsive parkinsonism and amyotrophic lateral sclerosis (ALS) are described herein. Family A expressed good dopaminergic treatment-responsive parkinsonism as an initial manifestation and developed mild cerebellar ataxia with additional movements, including dystonic gait and unusual oscillatory movement of the trunk, during the disease course. The proband of family B presented as probable ALS with cerebellar atrophy on brain MRI, with a positive family history (a brother with typical cerebellar ataxia) and genetic confirmation for SCA8.
Conclusions
Our findings support that the non-ataxic phenotypes could be caused by a mutation of the SCA8 locus which might affect neurons other than the cerebellum.
doi:10.3988/jcn.2013.9.4.274
PMCID: PMC3840139  PMID: 24285970
Spinocerebellar ataxia 8; phenotype; Parkinson's disease; Amyotrophic lateral sclerosis; clinical heterogeneity
13.  Deranged Calcium Signaling in Purkinje Cells and Pathogenesis in Spinocerebellar Ataxia 2 (SCA2) and Other Ataxias 
Cerebellum (London, England)  2012;11(3):630-639.
Spinocerebellar ataxias (SCAs) constitute a heterogeneous group of more than 30 autosomal-dominant genetic and neurodegenerative disorders. SCAs are generally characterized by progressive ataxia and cerebellar atrophy. Although all SCA patients present with the phenotypic overlap of cerebellar atrophy and ataxia, 17 different gene loci have so far been implicated as culprits in these SCAs. It is not currently understood how mutations in these 17 proteins lead to the cerebellar atrophy and ataxia. Several pathogenic mechanisms have been studied in SCAs but there is yet to be a promising target for successful treatment of SCAs. Emerging research suggests that a fundamental cellular signaling pathway is disrupted by a majority of these mutated genes, which could explain the characteristic death of Purkinje cells, cerebellar atrophy, and ataxia that occur in many SCAs. We propose that mutations in SCA genes cause disruptions in multiple cellular pathways but the characteristic SCA pathogenesis does not begin until calcium signaling pathways are disrupted in cerebellar Purkinje cells either as a result of an excitotoxic increase or a compensatory suppression of calcium signaling. We argue that disruptions in Purkinje cell calcium signaling lead to initial cerebellar dysfunction and ataxic sympoms and eventually proceed to Purkinje cell death. Here, we discuss a calcium hypothesis of Purkinje cell neurodegeneration in SCAs by primarily focusing on an example of spinocerebellar ataxia 2 (SCA2). We will also present evidence linking deranged calcium signaling to the pathogenesis of other SCAs (SCA1, 3, 5, 6, 14, 15/16) that lead to significant Purkinje cell dysfunction and loss in patients.
doi:10.1007/s12311-010-0182-9
PMCID: PMC3257360  PMID: 20480274
Purkinje cell; Calcium; Ataxia; Polyglutamine; Excitotoxicity; Neurodegeneration; SCA2
14.  CAG repeat instability, cryptic sequence variation and pathogeneticity: evidence from different loci. 
Different aspects of expanded polyglutamine tracts and of their pathogenetic role are taken into consideration here. (i) The (CAG)n length of wild-type alleles of the Huntington disease gene was analysed in instability-prone tumour tissue from colon cancer patients to test whether the process leading to the elongation of alleles towards the expansion range involves single-unit stepwise mutations or larger jumps. The analysis showed that length changes of a single unit had a relatively low frequency. (ii) The observation of an expanded spinocerebellar ataxia (SCA)1 allele with an unusual pattern of multiple CAT interruptions showed that cryptic sequence variations are critical not only for sequence length stability but also for the expression of the disease phenotype. (iii) Small expansions of the (CAG)n sequence at the CACNA1A gene have been reported as causing SCA6. The analysis of families with SCA6 and episodic ataxia type 2 showed that these phenotypes are, in fact, expressions of the same disorder caused either by point mutations or by small (CAG)n expansions. A gain of function has been hypothesized for all proteins containing an expanded polyglutamine stretch, including the alpha 1A subunit of the voltage-gated calcium channel type P/Q coded by the CACNA1A gene. Because point mutations at the same gene with similar phenotypic consequences are highly unlikely to have this effect, an alternative common pathogenetic mechanism for all these mutations, including small expansions, can be hypothesized.
PMCID: PMC1692606  PMID: 10434311
15.  Mutation detection in Machado-Joseph disease using repeat expansion detection. 
Molecular Medicine  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.
Images
PMCID: PMC2230032  PMID: 8900536
16.  Spinocerebellar Ataxia Type 10: Frequency of epilepsy in a large sample of Brazilian patients 
Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant disorder caused by an ATTCT repeat intronic expansion in the SCA10 gene. SCA 10 has been reported in Mexican, Brazilian, Argentinean and Venezuelan families. Its phenotype is overall characterized by cerebellar ataxia and epilepsy. Interestingly, Brazilian patients reported so far showed pure cerebellar ataxia, without epilepsy. Here, authors provide a systematic analysis of the presence, frequency and electroencephalographic presentation of epilepsy among 80 SCA10 patients from 10 Brazilian families. Overall, the frequency of epilepsy was considered rare, been found in 3.75 % of the cases while this finding in populations from other geographic areas reaches 60% of SCA10 cases.
doi:10.1002/mds.23324
PMCID: PMC3000879  PMID: 20818609
Spinocerebellar ataxia type 10; SCA; autosomal dominant cerebellar ataxia; epilepsy
17.  CAG Repeats Determine Brain Atrophy in Spinocerebellar Ataxia 17: A VBM Study 
PLoS ONE  2011;6(1):e15125.
Background
Abnormal repeat length has been associated with an earlier age of onset and more severe disease progression in the rare neurodegenerative disorder spinocerebellar ataxia 17 (SCA17).
Methodology/Principal Findings
To determine whether specific structural brain degeneration and rate of disease progression in SCA17 might be associated with the CAG repeat size, observer-independent voxel-based morphometry was applied to high-resolution magnetic resonance images of 16 patients with SCA17 and 16 age-matched healthy controls. The main finding contrasting SCA17 patients with healthy controls demonstrated atrophy in the cerebellum bilaterally. Multiple regression analyses with available genetic data and also post-hoc correlations revealed an inverse relationship again with cerebellar atrophy. Moreover, we found an inverse relationship between the CAG repeat length and rate of disease progression.
Conclusions
Our results highlight the fundamental role of the cerebellum in this neurodegenerative disease and support the genotype-phenotype relationship in SCA17 patients. Genetic factors may determine individual susceptibility to neurodegeneration and rate of disease progression.
doi:10.1371/journal.pone.0015125
PMCID: PMC3023761  PMID: 21311576
18.  Absence of unidentified CAG repeat expansion in patients with Huntington's disease-like phenotype 
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded (CAG)n repeat on the huntingtin gene. It is characterised by motor, psychiatric and cognitive disturbances. Diagnosis can be confirmed by direct genetic testing, which is highly sensitive and specific and is now considered definitive. This study focused on 21 patients presenting with a clinical phenotype showing strong similarity to HD, but who do not have an expanded CAG in the huntingtin gene. However, other possible diagnoses could be evoked for most of them. Seven patients (3.5% of our cohort) could be considered as phenocopies of HD with no alternative diagnosis. Samples were screened for other triplet repeat diseases with similar presentation (DRPLA, SCA-1, SCA-2, SCA-3, SCA-6, and SCA-7) and were all negative. The repeat expansion detection technique (RED) was used to detect uncloned CAG repeat expansions and samples were also analysed by polymerase chain reaction for expansions of the polymorphic CAG-ERDA-1 and CTG18.1 trinucleotide repeats. RED expansion (>40 repeats) was detected in only one patient. The results suggest that unstable CAG/CTG repeat expansions corresponding to known or unknown sequences are not involved in the aetiology of HD-like disorders. It is hypothesised that some of these phenocopies could correspond to mutations in other unidentified genes with other unstable repeats (different from CAG) or in unknown genes with other mutations.


doi:10.1136/jnnp.68.5.672
PMCID: PMC1736926  PMID: 10766906
19.  Positive Selection of a Pre-Expansion CAG Repeat of the Human SCA2 Gene 
PLoS Genetics  2005;1(3):e41.
A region of approximately one megabase of human Chromosome 12 shows extensive linkage disequilibrium in Utah residents with ancestry from northern and western Europe. This strikingly large linkage disequilibrium block was analyzed with statistical and experimental methods to determine whether natural selection could be implicated in shaping the current genome structure. Extended Haplotype Homozygosity and Relative Extended Haplotype Homozygosity analyses on this region mapped a core region of the strongest conserved haplotype to the exon 1 of the Spinocerebellar ataxia type 2 gene (SCA2). Direct DNA sequencing of this region of the SCA2 gene revealed a significant association between a pre-expanded allele [(CAG)8CAA(CAG)4CAA(CAG)8] of CAG repeats within exon 1 and the selected haplotype of the SCA2 gene. A significantly negative Tajima's D value (−2.20, p < 0.01) on this site consistently suggested selection on the CAG repeat. This region was also investigated in the three other populations, none of which showed signs of selection. These results suggest that a recent positive selection of the pre-expansion SCA2 CAG repeat has occurred in Utah residents with European ancestry.
Synopsis
Natural selection ultimately acts on the genetic variants existing among human populations. Therefore, there are “footprints” that the selective force has left behind in the human genome. In this study, Yu et al. identified an extremely large region on Chromosome 12 that is under positive selection in Utah residents with European ancestry by characterizing the correlation patterns of genomic variants. Further analyses on this interval suggested that selection centered on one of the many forms of Spinocerebellar ataxia type-2 (SCA2) gene. The selected form was next demonstrated to associate with one short version of the disease-causing CAG repeat in the SCA2 gene. These results suggest that the CAG repeat was positively selected. An abnormally long version of CAGs can cause SCA2, a neurodegenerative disease that severely impairs the abilities of body movement. The authors showed how they unraveled natural selection acting on the SCA2 gene. Their findings might lead to the discovery of the biological functions of this gene and its CAG repeat. This kind of study holds potential to facilitate the finding of common disease genes.
doi:10.1371/journal.pgen.0010041
PMCID: PMC1239938  PMID: 16205789
20.  Analysis of spinocerebellar ataxia type 2 gene and haplotype analysis: (CCG)1- 2 polymorphism and contribution to founder effect 
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.


Keywords: spinocerebellar ataxia type 2; CCG repeat polymorphism; founder effect
PMCID: PMC1734293  PMID: 10051008
21.  The effect of CAT trinucleotide interruptions on the age at onset of spinocerebellar ataxia type 1 (SCA1) 
Journal of Medical Genetics  1999;36(7):546-548.
The effect of CAT trinucleotide interruptions in the CAG trinucleotide repeats of the SCA1 gene on the age at onset of spinocerebellar ataxia type 1 (SCA1) was investigated. The number of CAG repeats in SCA1 was determined by polymerase chain reaction (PCR) analysis, and the presence of CAT interruptions was assessed on the basis of the sensitivity of the PCR products to the restriction endonuclease SfaNI, which recognises CAT trinucleotides. Only one in 17 expanded SCA1 alleles from 17 SCA1 patients was interrupted by CAT. The SfaNI sensitive SCA1 allele from this single patient contained 58 CAG repeats, which would predict an age at onset of SCA1 of 22.0 years, in contrast to the actual 50 years. In addition, the brain stem atrophy of this patient was mild compared with that of a patient with 52 uninterrupted CAG repeats. A sequence analysis showed that the repeat portion of the patient contained (CAG)45CATCAG CAT(CAG)10. From these results, we suggest that the age at onset of SCA1 is not determined by the total number of CAG repeats (58) but by the number of uninterrupted CAG repeats. 


Keywords: SCA1; CAG repeat; CAT interruption; SfaNI
PMCID: PMC1734401  PMID: 10424816
22.  Progress in pathogenesis studies of spinocerebellar ataxia type 1. 
Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited disorder characterized by progressive loss of coordination, motor impairment and the degeneration of cerebellar Purkinje cells, spinocerebellar tracts and brainstem nuclei. Many dominantly inherited neurodegenerative diseases share the mutational basis of SCA1: the expansion of a translated CAG repeat coding for glutamine. Mice lacking ataxin-1 display learning deficits and altered hippocampal synaptic plasticity but none of the abnormalities seen in human SCA1; mice expressing ataxin-1 with an expanded CAG tract (82 glutamine residues), however, develop Purkinje cell pathology and ataxia. These results suggest that mutant ataxin-1 gains a novel function that leads to neuronal degeneration. This novel function might involve aberrant interaction(s) with cell-specific protein(s), which in turn might explain the selective neuronal pathology. Mutant ataxin-1 interacts preferentially with a leucine-rich acidic nuclear protein that is abundantly expressed in cerebellar Purkinje cells and other brain regions affected in SCA1. Immunolocalization studies in affected neurons of patients and SCA1 transgenic mice showed that mutant ataxin-1 localizes to a single, ubiquitin-positive nuclear inclusion (NI) that alters the distribution of the proteasome and certain chaperones. Further analysis of NIs in transfected HeLa cells established that the proteasome and chaperone proteins co-localize with ataxin-1 aggregates. Moreover, overexpression of the chaperone HDJ-2/HSDJ in HeLa cells decreased ataxin-1 aggregation, suggesting that protein misfolding might underlie NI formation. To assess the importance of the nuclear localization of ataxin-1 and its role in SCA1 pathogenesis, two lines of transgenic mice were generated. In the first line, the nuclear localization signal was mutated so that full-length mutant ataxin-1 would remain in the cytoplasm; mice from this line did not develop any ataxia or pathology. This suggests that mutant ataxin-1 is pathogenic only in the nucleus. To assess the role of the aggregates, transgenic mice were generated with mutant ataxin-1 without the self-association domain (SAD) essential for aggregate formation. These mice developed ataxia and Purkinje cell abnormalities similar to those seen in SCA1 transgenic mice carrying full-length mutant ataxin-1, but lacked NIs. The nuclear milieu is thus a critical factor in SCA1 pathogenesis, but large NIs are not needed to initiate pathogenesis. They might instead be downstream of the primary pathogenic steps. Given the accumulated evidence, we propose the following model for SCA1 pathogenesis: expansion of the polyglutamine tract alters the conformation of ataxin-1, causing it to misfold. This in turn leads to aberrant protein interactions. Cell specificity is determined by the cell-specific proteins interacting with ataxin-1. Submicroscopic protein aggregation might occur because of protein misfolding, and those aggregates become detectable as NIs as the disease advances. Proteasome redistribution to the NI might contribute to disease progression by disturbing proteolysis and subsequent vital cellular functions.
PMCID: PMC1692607  PMID: 10434309
23.  Genetics of the SCA6 gene in a large family segregating an autosomal dominant "pure" cerebellar ataxia 
Journal of Medical Genetics  1999;36(2):148-151.
Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant cerebellar degeneration caused by the expansion of a CAG trinucleotide repeat in the CACNA1A gene. Mutations in patients are characterised by expanded alleles of between 21 and 30 repeat units and by extreme gonadal stability when transmitted from parents to children. We have investigated the SCA6 mutation in a large Spanish kindred in which previously reported spinocerebellar SCA genes and loci had been excluded. We observed a 23 CAG repeat expanded allele in the 13 clinically affected subjects and in three out of 10 presymptomatic at risk subjects. Transmission of the mutant allele was stable in six parent to child pairs and in 29 meioses through the pedigree. Linkage analysis with the SCA6-CAG polymorphism and marker D19S221 confirmed the location of SCA6 on chromosome 19p13. The molecular findings in this large family confirm the expansion of the CAG repeat in the CACNA1A gene as the cause of SCA6 and the high meiotic stability of the repeat.


Keywords: spinocerebellar ataxia 6; meiotic stability; presymptomatic diagnosis
PMCID: PMC1734305  PMID: 10051016
24.  Caring for Machado-Joseph Disease: current understanding and how to help patients 
Machado-Joseph disease or spinocerebellar ataxia 3 (MJD/SCA3) is a clinically heterogeneous, neurodegenerative disorder characterized by varying degrees of ataxia, ophthalmoplegia, peripheral neuropathy, pyramidal dysfunction and movement disorder. MJD/SCA3 is caused by a CAG repeat expansion mutation in the protein coding region of the ATXN3 gene located at chromosome 14q32.1. Current hypotheses regarding pathogenesis favor the view that mutated ataxin-3, with its polyglutamine expansion, is prone to adopt an abnormal conformation, engage in altered protein-protein interactions and aggregate. Expanded CAG repeat length correlates with the range and severity of the clinical manifestations and inversely correlates with age of disease onset. Though MJD/SCA3 is classically described as affecting the cerebellum, brain stem and basal ganglia, recent neuropathology and neuroimaging series demonstrate involvement of other areas such as the thalamus and cerebral cortex. Clinically, much emphasis has been placed in the description and recognition of the non-motor symptoms observed in these patients, such as pain, cramps, fatigue and depression. Currently, no disease modifying treatment exists for MJD/SCA3. Standard of care includes genetic counseling, exercise/physical therapy programs, and speech and swallow evaluation. Symptomatic treatment for clinical findings such as depression, sleep disorders, parkinsonism, dystonia, cramps, and pain is important to improve the quality of life for those with MJD/SCA3.
doi:10.1016/j.parkreldis.2009.08.012
PMCID: PMC2818316  PMID: 19811945
Spinocerebellar ataxia type 3; SCA3; Machado-Joseph disease; CAG
25.  CAG repeat RNA as an auxiliary toxic agent in polyglutamine disorders 
RNA Biology  2011;8(4):565-571.
Over 20 genetic loci with abnormal expansions of short tandem repeats have been associated with human hereditary neurological diseases. Of these, specific trinucleotide repeats located in non-coding and coding regions of individual genes implicated in these disorders are strongly overrepresented. Expansions of CTG, CGG and CAG repeats are linked to, respectively, myotonic dystrophy type 1 (DM1), fragile X-associated tremor/ataxia syndrome (FXTAS), as well as Huntington's disease (HD) and a number of spinocerebellar ataxias (SCAs). Expanded CAG repeats in translated exons trigger the most disorders for which a protein gain-of-function mechanism has been proposed to explain neurodegeneration by polyglutamine-rich (poly-Q) proteins. However, the results of last years showed that RNA composed of mutated CAG repeats can also be toxic and contribute to pathogenesis of polyglutamine disorders through an RNA-mediated gain-of-function mechanism. This mechanism has been best characterized in the non-coding repeat disorder DM1 and is also implicated in several other diseases, such as FXTAS, spinocerebellar ataxia type 8 (SCA8), Huntington's disease-like 2 (HDL2), as well as in myotonic dystrophy type 2 (DM2), spinocerebellar ataxia type 10 (SCA10) and type 31 (SCA31). in this review, we summarize recent findings that emphasize the participation of coding mutant CAG repeat RNA in the pathogenesis of polyglutamine disorders, and we discuss the basis of an RNA gain-of-function model in non-coding diseases such as DM1, FXTAS and SCA8.
doi:10.4161/rna.8.4.15397
PMCID: PMC3225975  PMID: 21593608
DM1; FXTAS; MBNL sequestration; polyglutamine disorders; RNA gain-of-function; SCA8

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