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At least 19 recordsLinked to original sources
PubMed2000

Expression analysis of ataxin-7 mRNA and protein in human brain: evidence for a widespread distribution and focal protein accumulation.

Spinocerebellar ataxia 7 (SCA7) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG-trinucleotide repeat in the coding region of the SCA7 gene. The expansion is translated into an extended polyglutamine stretch in the protein ataxin-7, a protein of unknown function. By Northern blot analysis expression of ataxin-7 was detected in numerous regions of human brain and some peripheral tissues. It is unknown, however, if ataxin-7 is enriched at sites of the SCA7 pathology. We studied the regional and cellular expression pattern of ataxin-7 at the mRNA level by in situ hybridization histochemistry in normal human brain. Furthermore we used a monoclonal and two polyclonal antibodies raised against the normal ataxin-7 to establish the distribution of this protein in brain, retina and peripheral organs. At the mRNA level ataxin-7 was preferentially expressed in neurons; the regional distribution reflected neuronal packing density. Ataxin-7 immunoreactivity (IR) was similarly widely expressed. In most neurons, ataxin-7 IR was preferentially localized to the cytoplasmatic compartment although some nuclear ataxin-7 IR was detected in most neurons. A more intense and more prominently nuclear ataxin-7 IR was observed in neurons of the pons and the inferior olive, brain regions severly affected by the disease, suggesting that the subcellular localization and abundance of ataxin-7 is regulated in a regionally specific way. Since neurons displaying more intense and more prominently nuclear ataxin-7 IR belonged to the class of susceptible cells in SCA7, an enrichment of normal ataxin-7 in the nuclear compartment may contribute to neurodegeneration. However not all sites of SCA7 pathology displayed a strong cytoplasmatic and nuclear immunoreactivity.

Ataxin-7↗
PubMed2000

Conserved phosphoprotein interaction motif is functionally interchangeable between ataxin-7 and arrestins.

Olivopontocerebellar atrophy with retinal degeneration is a hereditary neurodegenerative disorder that belongs to the subtype II of the autosomal dominant cerebellar ataxias and is characterized by early-onset cerebellar and macular degeneration preceded by diagnostically useful tritan colorblindness. The gene mutated in the disease (SCA7) has been mapped to chromosome 3p12-13.5, and positional cloning identified the cause of the disease as CAG repeat expansion in this gene. The SCA7 gene product, ataxin-7, is an 897 amino acid protein with an expandable polyglutamine tract close to its N-terminus. No clues to ataxin-7 function have been obtained from sequence database searches. Here we report that ataxin-7 has a motif of ca. 50 amino acids, related to the phosphate-binding site of arrestins. To test the relevance of this sequence similarity, we introduced the putative ataxin-7 phosphate-binding site into visual arrestin and beta-arrestin. Both chimeric arrestins retain receptor-binding affinity and show characteristic high selectivity for phosphorylated activated forms of rhodopsin and beta-adrenergic receptor, respectively. Although the insertion of a Gly residue (absent in arrestins but present in the putative phosphate-binding site of ataxin-7) disrupts the function of visual arrestin-ataxin-7 chimera, it enhances the function of beta-arrestin-ataxin-7 chimera. Taken together, our data suggest that the arrestin-like site in the ataxin-7 sequence is a functional phosphate-binding site. The presence of the phosphate-binding site in ataxin-7 suggests that this protein may be involved in phosphorylation-dependent binding to its protein partner(s) in the cell.

Amino Acid Sequence↗
PubMed1999

Identification and localization of ataxin-7 in brain and retina of a patient with cerebellar ataxia type II using anti-peptide antibody.

Autosomal dominant cerebellar ataxias (ADCAs) are a complex group of neurodegenerative disorders characterized by progressive degeneration of the cerebellum, brain stem and spinal cord. The spinocerebellar ataxia type 7 (SCA7) is associated with pigmentary macular dystrophy and retinal degeneration leading to blindness caused by a CAG/polyglutamine (polyGln) expansion in the coding region of the SCA7 gene/protein. The SCA7 gene codes for ataxin-7, a protein of unknown function. To investigate its cellular and subcellular localization, we have developed a sequence-specific polyclonal antibody against the N-terminal part of the protein. Immunohistochemical analysis indicated that ataxin-7 accumulates as single nuclear inclusion (NI) in the cells of the brain and retina of a SCA7 patient but not of controls. The 1C2 antibody, directed against expanded polyGln, confirmed the aggregation of mutant ataxin-7 in these NIs. Furthermore, ubiquitin was found in these aggregates, suggesting that mutant ataxin-7 is a target for ubiquitin-dependent proteolysis, but resistant to removal. Electron microscopic studies using immunogold labeling showed that ataxin-7 immunoreactive NIs appear as dense aggregates containing a mixture of granular and filamentary structures. Together, these data confirm the presence of NIs in brain and retina of a SCA7 patient, a common characteristic of disorders caused by expanded CAG/polyGln repeats.

Adult↗
PubMed1999

Nuclear localization of the spinocerebellar ataxia type 7 protein, ataxin-7.

Spinocerebellar ataxia type 7 (SCA7) belongs to a group of neurological disorders caused by a CAG repeat expansion in the coding region of the associated gene. To gain insight into the pathogenesis of SCA7 and possible functions of ataxin-7, we examined the subcellular localization of ataxin-7 in transfected COS-1 cells using SCA7 cDNA clones with different CAG repeat tract lengths. In addition to a diffuse distribution throughout the nucleus, ataxin-7 associated with the nuclear matrix and the nucleolus. The location of the putative SCA7 nuclear localization sequence (NLS) was confirmed by fusing an ataxin-7 fragment with the normally cytoplasmic protein chicken muscle pyruvate kinase. Mutation of this NLS prevented protein from entering the nucleus. Thus, expanded ataxin-7 may carry out its pathogenic effects in the nucleus by altering a matrix-associated nuclear structure and/or by disrupting nucleolar function.

Animals↗
PubMed2000

Frequency of SCA1, SCA2, SCA3/MJD, SCA6, SCA7, and DRPLA CAG trinucleotide repeat expansion in patients with hereditary spinocerebellar ataxia from Chinese kindreds.

OBJECTIVE: To assess the frequency of SCA1 (spinocerebellar ataxia type 1), SCA2, SCA3/MJD (spinocerebellar ataxia type 3/Machado-Joseph disease), SCA6, SCA7, and DRPLA (dentatorubropallidoluysian atrophy) CAG trinucleotide repeat expansions [(CAG)n] among persons diagnosed with hereditary SCA from Chinese families. PATIENTS AND METHODS: Spinocerebellar ataxia type 1, SCA2, SCA3/MJD, SCA6, SCA7, and DRPLA (CAG)n mutation were detected with the polymerase chain reaction, highly denaturing polyacrylamide gel electrophoresis, and silver staining technique in 167 patients with autosomal dominant SCA from 85 Chinese families and 37 patients with sporadic SCA. RESULTS: Spinocerebellar ataxia type 1 (CAG)n mutation in 7 patients from 4 kindreds (4.70%) was expanded to 53 to 62 repeats. Spinocerebellar ataxia type 2 (CAG)n mutation in 12 patients from 5 kindreds (5.88%) was expanded to 42 to 47 repeats. Spinocerebellar ataxia type 3/Machado-Joseph disease (CAG)n mutation in 83 patients from 41 kindreds (48.23%) was expanded to 68 to 83 repeats. Sixty-five patients from 35 kindreds (41.19%) and 37 patients with sporadic SCA did not test positive for SCA1, SCA2, SCA3/MJD, SCA6, SCA7, or DRPLA. There was a predictable inverse relationship between the number of CAG repeats and the age at onset for SCA3/MJD and SCA2. Clinically, dementia and hyporeflexia were more frequent in patients with SCA2, while spasticity, hyperreflexia, and Babinski signs were more frequent in patients with SCA3/ MJD, and those might be helpful in clinical work to primarily distinguish patients with SCA3/MJD and SCA2 from others with different types of SCA. CONCLUSIONS: The frequency of SCA3/MJD is substantially higher than that of SCA1 and SCA2 in patients with autosomal dominant SCA from Chinese kindreds, who are non-Portuguese. Clinical expressions of the various types of SCAs overlap one another; therefore, for clinical study it is important to make a gene diagnosis and genetic classification for patients with SCA.

Adolescent↗
PubMed2000

Analysis of CAG repeats in SCA1, SCA2, SCA3, SCA6, SCA7 and DRPLA loci in spinocerebellar ataxia patients and distribution of CAG repeats at the SCA1, SCA2 and SCA6 loci in nine ethnic populations of eastern India.

To identify various subtypes of spinocerebellar ataxias (SCAs) among 57 unrelated individuals clinically diagnosed as ataxia patients we analysed the SCA1, SCA2, SCA3, SCA6, SCA7 and DRPLA loci for expansion of CAG repeats. We detected CAG repeat expansion in 6 patients (10.5%) at the SCA1 locus. Ten of the 57 patients (17.5%) had CAG repeat expansion at the SCA2 locus, while four had CAG expansion at the SCA3/MJD locus (7%). At the SCA6 locus there was a single patient (1.8%) with 21 CAG repeats. We have not detected any patient with expansion in the SCA7 and DRPLA loci. To test whether the frequencies of the large normal alleles in SCA1, SCA2 and SCA6 loci can reflect some light on prevalence of the subtypes of SCAs we studied the CAG repeat variation in these loci in nine ethnic sub-populations of eastern India from which the patients originated. We report here that the frequency of large normal alleles (>31 CAG repeats) in SCA1 locus to be 0.211 of 394 chromosomes studied. We also report that the frequency of large normal alleles (>22 CAG repeats) at the SCA2 locus is 0.038 while at the SCA6 locus frequency of large normal alleles (>13 repeats) is 0.032. We discussed our data in light of the distribution of normal alleles and prevalence of SCAs in the Japanese and white populations.

Adolescent↗
PubMed1999

Spinocerebellar ataxias in Spanish patients: genetic analysis of familial and sporadic cases. The Ataxia Study Group.

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, 35 to 46 [corrected] 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.

Adult↗
PubMed1999

Spinocerebellar ataxia type 7 (SCA7) - correlations between phenotype and genotype in one large Belgian family.

Spinocerebellar ataxia type 7 (SCA7), in which the degenerative process also affect the retina, belongs to the category of the autosomal dominant cerebellar ataxia type II (ADCA II). We have described the neuropathology of this condition [Martin JJ, Van Regemorter N, Krols L, Brucher JM, de Barsy T, Szliwowski H, et al. On an autosomal dominant form of retino-cerebellar degeneration: an autopsy study of five patients in one family. Acta Neuropathol (Berl) 1994;88:277-286] in a very large Belgian family (CA-1). We have observed anticipation in the age of onset with increasing severity of the symptoms in consecutive generations. The SCA7 gene was mapped to chromosome 3p12-13 [David G, Abbas N, Stevanin G, Dürr A, Yvert G, Cancel G, et al. Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nat Genet 1997;17:65-70; Del-Favero J, Krols L, Michalik A, Theuns J, Löfgren A, Goossens D, et al. Molecular genetic analysis of autosomal dominant cerebellar ataxia with retinal degeneration (ADCA type II) caused by CAG triplet repeat expansion. Hum Mol Genet 1998;7:177-186], and the gene identified. SCA7 is a new gene of unknown function that contains an expansion of CAG repeats in SCA7 patients. During the procedure of positional cloning, we examined 26 patients belonging to the CA-1 family and realized, in some of them, an ophthalmologic examination and neuro-imaging of the brain. This allowed us to differentiate four groups: (1) asymptomatic young carriers with 38 to 43 CAG repeats; (2) mildly symptomatic, older patients with 38-41 CAG repeats; (3) patients with the full-blown picture of SCA7 and age of onset during adolescence, with 54-55 CAG repeats; (4) children with early onset and rapid fatal course of the disease who had over 55 CAG repeats. We were able to draw correlations between clinical phenotype, age at onset and CAG repeat number and to make predictions, to some extent, as to the clinical course of the disease in new patients.

Adult↗
PubMed1998

Rapid cloning of expanded trinucleotide repeat sequences from genomic DNA.

Trinucleotide repeat expansions have been shown to cause a number of neurodegenerative diseases. A hallmark of most of these diseases is the presence of anticipation, a decrease in the age at onset in consecutive generations due to the tendency of the unstable trinucleotide repeat to lengthen when passed from one generation to the next. The involvement of trinucleotide repeat expansions in a number of other diseases--including familial spastic paraplegia, schizophrenia, bipolar affective disorder and spinocerebellar ataxia type 7 (SCA7; ref. 10)--is suggested both by the presence of anticipation and by repeat expansion detection (RED) analysis of genomic DNA samples. The involvement of trinucleotide expansions in these diseases, however, can be conclusively confirmed only by the isolation of the expansions present in these populations and detailed analysis to assess each expansion as a possible pathogenic mutation. We describe a novel procedure for quick isolation of expanded trinucleotide repeats and the corresponding flanking nucleotide sequence directly from small amounts of genomic DNA by a process of Repeat Analysis, Pooled Isolation and Detection of individual clones containing expanded trinucleotide repeats (RAPID cloning). We have used this technique to clone the pathogenic SCA7 CAG expansion from an archived DNA sample of an individual affected with ataxia and retinal degeneration.

Ataxia↗
PubMed1997

Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion.

The gene for spinocerebellar ataxia 7 (SCA7) has been mapped to chromosome 3p12-13. By positional cloning, we have identified a new gene of unknown function containing a CAG repeat that is expanded in SCA7 patients. On mutated alleles, CAG repeat size is highly variable, ranging from 38 to 130 repeats, whereas on normal alleles it ranges from 7 to 17 repeats. Gonadal instability in SCA7 is greater than that observed in any of the seven known neuro-degenerative diseases caused by translated CAG repeat expansions, and is markedly associated with paternal transmissions. SCA7 is the first such disorder in which the degenerative process also affects the retina.

Adult↗
PubMed1999

Multiple origins of the spinocerebellar ataxia 7 (SCA7) mutation revealed by linkage disequilibrium studies with closely flanking markers, including an intragenic polymorphism (G3145TG/A3145TG).

Spinocerebellar ataxia 7 (SCA7) is a neurodegenerative disease characterised by the association of cerebellar ataxia and, in most patients, progressive macular degeneration leading to loss of autonomy and blindness. The patients die after 5-30 years of evolution. The cause of the disease has been identified as a (CAG)n repeat expansion in the coding sequence of the SCA7 gene on chromosome 3p. De novo mutations occur on intermediate-sized alleles carrying from 28 to 35 CAG repeats. Neomutations explain the persistence of the disease in spite of the great instability of the repeat sequence which results in the appearance of juvenile onset patients and the extinction of the disease within families. This rare disorder has been reported in a wide variety of countries and ethnic groups. In a large number of SCA7 families (n = 41) of different origins, we have determined the haplotypes segregating with the mutation of several microsatellite markers close to the SCA7 gene and of a new intragenic polymorphism (G3145TG/A3145TG). Four different haplotypes were found for centromeric markers (G3145TG/A3145TG-D3S1287-D3S3635) in the majority of the kindreds from four different geographic regions: A-2-4 in Korea; A-3-6 in North Africa, B-3-6 in continental Europe and A-4-6 in the UK and USA. The haplotypes in the Jamaican, Filipino, Brazilian and German families were different, suggesting that independent regional founders are at the origin of the SCA7 mutation in each population. Two different haplotypes were observed, however, in two families from the same rural area in central Italy in which de novo SCA7 mutations on intermediate alleles have been observed, suggesting the existence of different pools of at-risk chromosomes in this population.

Alleles↗
PubMed1999

Molecular and clinical study of 18 families with ADCA type II: evidence for genetic heterogeneity and de novo mutation.

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.

Age of Onset↗
PubMed1998

Analysis of the dynamic mutation in the SCA7 gene shows marked parental effects on CAG repeat transmission.

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.

Adolescent↗
PubMed1998

Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions.

Autosomal dominant cerebellar ataxia with progressive macular degeneration is caused by a CAG/glutamine repeat expansion in the SCA7 gene/protein. Neuronal intranuclear inclusions were detected in the brain of an early onset SCA7 case with the 1C2 antibody directed against an expanded polyglutamine domain. Nuclear inclusions were most frequent in the inferior olivary complex, a site of severe neuronal loss in SCA7. They were also observed in other brain regions, including the cerebral cortex, not considered to be affected in the disease. Using confocal microscopy we showed that some inclusions were ubiquitinated, but to varying degrees, ranging from <1% in the cerebral cortex to 60% in the inferior olive. In addition, we also observed cytoplasmic staining using the 1C2 antibody, particularly in the supramarginal gyrus, the hippocampus, the thalamus, the lateral geniculate body and the pontine nuclei. These data confirm that the presence of intranuclear inclusions in neurons is a common characteristic of disorders caused by CAG/polyglutamine expansions, but unlike what has been reported for Huntington's disease, SCA1 and SCA3/MJD, in SCA7 the inclusions were not restricted to the sites of severe neuronal loss.

Ataxin-7↗
PubMed1999

Very large (CAG)(n) DNA repeat expansions in the sperm of two spinocerebellar ataxia type 7 males.

Genetic anticipation, i.e. increasing disease severity and decreasing age of onset from one generation to the next, is observed in a number of diseases, including myotonic dystrophy type 1, Huntington's disease and several of the spinocerebellar ataxias. All of these disorders are associated with the expansion of a trinucleotide repeat and array length is positively correlated with disease severity and inversely correlated with the age of onset. The expanded repeat is highly unstable and continues to expand from one generation to the next, providing a molecular explanation for anticipation. Spinocerebellar ataxia type 7 (SCA7) is one of the latest additions to the list of triplet repeat diseases and is distinct from the other SCAs in that it is accompanied by retinal degeneration. Pedigree analyses have previously revealed that the SCA7 repeat is highly unstable and liable to expand, in particular when transmitted by a male. Surprisingly, though, an under-representation of male transmission has also been reported. We now demonstrate directly by single molecule analyses that the expanded repeat is extraordinarily unstable in the male germline and biased toward massive increases. Nearly all of the mutant sperm of two SCA7 males contain alleles that are so large that most of the affected offspring would at best have a severe infantile form of the disease. Indeed, the gross under-representation of such very large expanded alleles in patients suggests that a significant proportion of such alleles might be associated with embryonic lethality or dysfunctional sperm.

Alleles↗
PubMed1998

Molecular and clinical studies in SCA-7 define a broad clinical spectrum and the infantile phenotype.

OBJECTIVE: To screen for the SCA-7 mutation in autosomal dominant cerebellar ataxia (ADCA) families and study genotype/phenotype correlations. BACKGROUND: The association of cerebellar ataxia and progressive pigmentary macular dystrophy clinically defines a distinct form of ADCA classified as SCA-7. SCA-7 is caused by expansion of a highly unstable CAG repeat that lies in the coding region of a novel gene on chromosome 3p12-13. METHODS: We screened 51 ADCA kindreds, in which SCA-1, SCA-2, SCA-3, and SCA6 mutations had been excluded, for the SCA-7 mutation using primers that specifically amplify the SCA-7 CAG repeat. RESULTS: The SCA-7 mutation was identified in 10 independent families. Normal alleles ranged from 7 to 16 repeats; expanded alleles ranged from 41 to 306 repeats. One allele with 36 repeats was found in an asymptomatic individual carrying an at-risk haplotype. SCA-7 presents a wide spectrum of clinical features including visual loss, dementia, hypoacusia, severe hypotonia, and auditory hallucinations. Juvenile SCA-7 occurs on maternal and paternal transmission of the mutation, whereas the infantile form occurs only on paternal transmission. An infant of African American descent carried the largest SCA-7 expansion (306 CAG repeats) and had severe hypotonia, congestive heart failure, patent ductus arteriosus, cerebral and cerebellar atrophy, and visual loss. CONCLUSION: These data show a wide spectrum of phenotypic abnormalities in SCA-7 and define an infantile phenotype caused by the largest CAG repeat expansion described to date.

Adolescent↗