Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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We present linkage analysis on a large Swedish five-generation family of 15 affected individuals with autosomal dominant cerebellar ataxia (ADCA) associated with retinal degeneration and anticipation. Common clinical signs in this family include ataxia, dysarthria and severely impaired vision with the phenotype ADCA type II. Different subtypes of ADCA have proven difficult to classify clinically due to extensive phenotypic variability within and between families. Genetic analysis of a number of ADCA type I families shows that heterogeneity exists also genetically. During the last few years several types of ADCA type I have been localized and to date six genetically distinct forms have been identified including SCA1 (6p), SCA2 (12q), SCA3 and Machado-Joseph disease (MJD) (14q), SCA4 (16q), and finally SCA5 (11). We performed a genome-wide search of the Swedish ADCA type II family using a total of 270 microsatellite markers. Positive lod scores were obtained with a number of microsatellite markers located on chromosome 3p12-p21.1. Three markers gave lod scores over 3 with a maximum lod score of 4.53 achieved with the marker D3S1600. The ADCA type II gene could be restricted to a region of 32 cM by the markers D3S1547 and D3S1274.
Hum Mol Genet 1995 Aug
PMID:Localization of autosomal dominant cerebellar ataxia associated with retinal degeneration and anticipation to chromosome 3p12-p21.1. 758 86

Autosomal dominant cerebellar ataxia type 1 (ADCA1) is a clinical and genetic heterogeneous neurodegenerative disorder which leads to progressive cerebellar ataxia. One defective gene responsible for the disease was first localised to 6p (SCA1, spinocerebellar ataxia type 1) and the mutation has been more recently characterised. We have analysed the CAG-repeat mutation responsible for the SCA1 phenotype in a large Spanish kindred with 41 affected members, in which positive linkage with D6S89 was previously shown. All (10) clinically affected members analysed were heterozygous with one disease allele being between 41 to 57 CAG repeats, and the other in the normal range, from 6 to 39 repeats. Nine clinically unaffected individuals who were between the ages of 18 and 40, were found to have expansions of the CAG repeat (41 to 59), and 22 other 'at risk' individuals were found to have inherited the SCA1 gene with copies of the CAG repeat in the normal range. We have also observed that affected fathers passed on the mutated SCA1 gene with larger increases in the number of CAG repeats than affected mothers did. In one case a decrease in the number of CAG repeats (51 to 50) was detected in the transmission from the affected mother, and in two cases no change was observed in the transmission of a 41 allele repeat by a mother. As in the other disorders in which knowledge of the mutation has been obtained, analysis of the repeat expansion dramatically changes diagnosis of SCA1.
Hum Mol Genet 1993 Dec
PMID:Presymptomatic analysis of spinocerebellar ataxia type 1 (SCA1) via the expansion of the SCA1 CAG-repeat in a large pedigree displaying anticipation and parental male bias. 811 82

The autosomal dominant cerebellar ataxias have proved particularly difficult to classify due to the lack of phenotypic concordance both within and between families. Genetic heterogeneity has been established, and disease loci for spinal cerebellar ataxia have been assigned to chromosomes 6 (SCA1), 12 (SCA2) and 14 (Machado Joseph disease (MJD)). Genetic analysis performed on a large Thai kindred with autosomal dominant cerebellar ataxia, in which frontal lobe signs and dementia are commonly observed in affected family members, exclude linkage to the SCA1, SCA2 and MJD loci. This demonstrates that mutation in at least one further locus can cause spinal cerebellar ataxia, indicating the need for caution in the use of markers for predictive testing or prenatal diagnosis these disorders.
Hum Mol Genet 1994 Jan
PMID:Autosomal dominant cerebellar ataxia with dementia: evidence for a fourth disease locus. 816 21

The gene for one form of autosomal dominant spinal cerebellar ataxia (SCA1), is mapped by linkage to chromosome 6p, very close to the microsatellite locus D6S89. Eight large Italian kindreds segregating SCA1, as defined by very close linkage to D6S89, were genotyped with five microsatellite markers linked closely to D6S89, all mapping within a 6 cM interval on 6p. Multipoint linkage analysis and haplotypes from recombinants map SCA1 between two of these markers, D6S274 and D6S259, 5-6 cM apart. A single rare four marker haplotype within this interval shows linkage disequilibrium with the disease locus in southern Italy and is transmitted with SCA1 in five kindreds originating from this area.
Hum Mol Genet 1993 Sep
PMID:The gene for spinal cerebellar ataxia 1 (SCA1) is flanked by two closely linked highly polymorphic microsatellite loci. 824 61

Trinucleotide repeats at five disease loci (DM, DRPLA, HD, SBMA and SCA1) were surveyed in phenotypically normal individuals from three continental populations. This is the first analysis to examine the population dynamics of these five disease-related trinucleotide repeats in the same individuals from worldwide populations. Roughly half of all alleles observed at each locus are shared between all continental groups. For three loci, disease prevalence in each population corresponds with the number of alleles in the upper tail of the allele-size distribution. The allele-size distributions of African, Asian and Caucasian groups show a high degree of variation, and gene diversity estimates for trinucleotide repeat loci exceed estimates derived from dinucleotide or tetranucleotide repeats. Analyses that compared infinite alleles and stepwise mutation models suggest that normal variation at trinucleotide loci is not generated by stepwise mutation alone. Trees constructed for subpopulations using trinucleotide repeat loci show accurate continental clustering. Interpopulation genetic distance estimates show remarkable similarity to distance estimates produced from tetranucleotide repeats or nuclear restriction site polymorphisms. This finding is especially noteworthy in light of the fact that trinucleotide repeat polymorphisms at these loci can cause disease, while restriction site and tetranucleotide polymorphisms appear to be selectively neutral. In contrast, genetic distance estimates from trinucleotide loci are poorly correlated with genetic distance estimates from mitochondrial sequence data.
Hum Mol Genet 1995 Sep
PMID:Population genetics of trinucleotide repeat polymorphisms. 854 30

Expansion of trinucleotide CAG repeats coding for polyglutamine has been implicated in five neurodegenerative disorders, including spinocerebellar ataxia (SCA) 1 and SCA3 or Machado-Joseph disease (SCA3/MJD), two forms of type I autosomal dominant cerebellar ataxias (ADCA). Using the 1C2 antibody which specifically recognizes large polyglutamine tracts, particularly those that are expanded, we recently reported the detection of proteins with pathological glutamine expansions in lymphoblasts from another form of ADCA type I, SCA2, as well as from patients presenting with the distinct phenotype of ADCA type II. We now have screened a large series of patients with ADCA or isolated cases with cerebellar ataxia, for the presence of proteins with polyglutamine expansions. A 150 kDa SCA2 protein was detected in 16 out of 40 families with ADCA type I. This corresponds to 24% of all ADCA type I families, which is much more frequent than SCA1 in this series of patients (13%). The signal intensity of the SCA2 protein was negatively correlated to age at onset, as expected for an expanded and unstable trinucleotide repeat mutation. The disease segregated with markers closely linked to the SCA2 locus in all identified SCA2 families. In addition, a specific 130 kDa protein, which segregated with the disease, was detected in lymphoblasts of patients from nine families with ADCA type II. It was also visualized in the cerebral cortex of one of the patients, demonstrating its translation in the nervous system. Finally, no new disease-related proteins containing expanded polyglutamine tracts could be detected in lymphoblasts from the remaining patients with ADCA or isolated cases with cerebellar ataxia.
Hum Mol Genet 1996 Dec
PMID:Screening for proteins with polyglutamine expansions in autosomal dominant cerebellar ataxias. 896 39

Recently, moderate (CAG)>20 repeat expansions in the alpha1A-voltage-dependent calcium channel gene (CACNL1A4) have been identified in a previously unmapped type of SCA which has been named SCA6. We investigated the (CAG)n repeat length of the CACNL1A4 gene in 733 patients with sporadic ataxia and in 46 German families with dominantly inherited SCA which do not harbor the SCA1, SCA2, or MJD1/SCA3 mutation, respectively. The SCA6 (CAG)n expansion was identified in 32 patients most frequently with late manifestation of the disease. The (CAG)n stretch of the affected allele varied between 22 and 28 trinucleotide units and is therefore the shortest trinucleotide repeat expansion causing spinocerebellar ataxia. The (CAG)n repeat length is inversely correlated with the age at onset. In 11 parental transmissions of the expanded allele no repeat instability has been observed. Repeat instability was also not found for the normal allele investigating 431 meioses in the CEPH families. Analyzing 248 apparently healthy octogenerians revealed one allele of 18 repeats which is the longest normal CAG repeat in the CACNL1A4 gene reported. The SCA6 mutation causes the disease in approximately 10% of autosomal dominant SCA in Germany. Most importantly, the trinucleotide expansion was observed in four ataxia patients without obvious family history of the disease which necessitates a search for the SCA6 (CAG)n expansion even in sporadic patients.
Hum Mol Genet 1997 Aug
PMID:SCA6 is caused by moderate CAG expansion in the alpha1A-voltage-dependent calcium channel gene. 925 75

The basis for the highly specific neuronal vulnerability seen in Huntington's disease (HD) has not been determined. Recent studies have demonstrated that variation in HD protein expression occurs in the striatum, with affected regions showing increased HD immunoreactivity. Experiments in HD and SCA1 transgenic mice suggest a correlation between phenotypic severity and expression of the mutant transgene. To gain insights into control of HD gene expression, and to investigate the possibility of cell-cell differences in transcription, we have analysed the 5' upstream region of the HD gene in a neuronal (SK-N-SH) and a non-neuronal (JEG3) cell line. Reporter gene assays demonstrated the presence of a key positive-acting region apparently arising from two Sp1 sites in a tandem repeat acting synergistically. This site is polymorphic, and a single Sp1 site is associated with reduced levels of transcription. These experiments also reveal differences in control of expression between neuronal and non-neuronal cell lines.
Hum Mol Genet 1998 May
PMID:Functional analysis of the Huntington's disease (HD) gene promoter. 953 82

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.
Hum Mol Genet 1998 May
PMID:Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions. 953 97

A gene (cpd1) coding for the dimethylallyltryptophan synthase (DMATS) that catalyzes the first specific step in the biosynthesis of ergot alkaloids, was cloned from a strain of Claviceps purpurea that produces alkaloids in axenic culture. The derived gene product (CPD1) shows only 70% similarity to the corresponding gene previously isolated from Claviceps strain ATCC 26245, which is likely to be an isolate of C. fusiformis. Therefore, the related cpd1 most probably represents the first C. purpurea gene coding for an enzymatic step of the alkaloid biosynthetic pathway to be cloned. Analysis of the 3'-flanking region of cpd1 revealed a second, closely linked ergot alkaloid biosynthetic gene named cpps1, which codes for a 356-kDa polypeptide showing significant similarity to fungal modular peptide synthetases. The protein contains three amino acid-activating modules, and in the second module a sequence is found which matches that of an internal peptide (17 amino acids in length) obtained from a tryptic digest of lysergyl peptide synthetase 1 (LPS1) of C. purpurea, thus confirming that cpps1 encodes LPS1. LPS1 activates the three amino acids of the peptide portion of ergot peptide alkaloids during D-lysergyl peptide assembly. Chromosome walking revealed the presence of additional genes upstream of cpd1 which are probably also involved in ergot alkaloid biosynthesis: cpox1 probably codes for an FAD-dependent oxidoreductase (which could represent the chanoclavine cyclase), and a second putative oxidoreductase gene, cpox2, is closely linked to it in inverse orientation. RT-PCR experiments confirm that all four genes are expressed under conditions of peptide alkaloid biosynthesis. These results strongly suggest that at least some genes of ergot alkaloid biosynthesis in C. purpurea are clustered, opening the way for a detailed molecular genetic analysis of the pathway.
Mol Gen Genet 1999 Feb
PMID:Evidence for an ergot alkaloid gene cluster in Claviceps purpurea. 1007 Dec 19


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