Dentatorubral-pallidoluysian Atrophy Research Articles

An assay for characterizing in vitro the kinetics of polyglutamine aggregation.

The expansion of trinucleotide CAG repeat sequences has been shown to be the underlying cause of eight human neurodegenerative disorders, including Huntington’ s disease (HD), spinal and bulbar muscular atrophy (SBMA), dentatorubral-pallidoluysian atrophy (DRPLA), Machado-Joseph disease (MJD), and the spinocerebellar ataxias (SCAs)(for review see refs. [, , ]). These diseases are progressive disorders characterized by motor and/or cognitive impairments and distinctive pathological patterns of neuronal degeneration within the central nervous system (CNS). Each is caused by CAG codon expansion within a unique gene producing a polyglutamine (polyGln) tract enlargement in the target protein (, , ). All of these neurodegenerative disorders present a common feature: the accumulation of the polyGln repeat disease-related protein into neuronal intranuclear inclusions, which have become the neuropathological signature of polyGln disorders (, , ). Several lines of reasoning suggest strongly that the expanded polyGln tract is itself responsible for the pathogenesis. First, the disease-related proteins do not present any homology in either size or amino acid composition outside of the expanded polyGln tract (,, , ). Second, the severity of the disease increases with the length of the polyGln repeat. Third, the length of the polyGln sequence that triggers increased risk for developing the pathology is very similar for almost of these diseases (,,). Finally, transgenic animals expressing protein fragments with an expanded polyGln repeat exhibit neurodegenerative phenotypes reminiscent of disease symptoms (, , , , ).

Frequency of spinocerebellar ataxia mutations in the Kinki district of Japan.

To determine the frequencies of spinocerebellar ataxias (SCAs) in the Kinki district, the western part of the main island of Japan. One hundred and forty-three families with dominantly inherited ataxia and 220 patients with apparently sporadic cerebellar ataxia were examined for the SCA1, SCA2, SCA3/Machado-Joseph disease (MJD), SCA6, SCA7, SCA8, SCA12 and dentatorubral-pallidoluysian atrophy (DRPLA) mutations. Among the dominant families, SCA1 accounted for 3%, SCA2 for 4%, SCA3/MJD for 24%, SCA6 for 31% and DRPLA for 12%. Neither SCA7 nor SCA12 mutations were detected. Among the apparently sporadic patients, 15% were found to have expanded triplet repeats. Of these, the SCA6 mutation was most frequently detected. SCA6 is the most common SCA in the Kinki district of Japan. Comparison of our results with those from other regions of Japan and different countries shows geographic and ethnic variation in the frequency of SCAs.

DIRECT technologies for molecular cloning of genes containing expanded CAG repeats.

Expansions of unstable CAG/CTG trinucleotide repeats have been identified as a common pathogenic mechanism in a growing number of hereditary neurodegenerative diseases, including myotonic dystrophy, spinal and bulbar muscular atrophy, Huntington’s disease (HD), spinocerebellar ataxia type 1 (SCA1), dentatorubral-pallidoluysian atrophy (DRPLA), Machado-Joseph disease (MJD), SCA2, SCA6, SCA7, SCA8, SCA12, and SCA17 (reviewed in refs. , , , , , , ). From the viewpoint of clinical genetics, these diseases are characterized by anticipation, i.e., accelerating age at onset and increasing disease severity in successive generations. It has been discovered that anticipation is a result of intergenerational increase in the size of expanded CAG repeats. These observations suggest that many hereditary neurodegenerative diseases characterized by anticipation and the broad spectrum of the clinical presentations are likely to be caused by the unstable expansion of CAG repeats.

A pediatric patient with sporadic dentatorubral pallidoluysian atrophy

We report a 10-year-old girl with the juvenile type of dentatorubral pallidoluysian atrophy. There were no affected family members, suggesting a sporadic case. Deoxyribonucleic acid analysis for the dentatorubral pallidoluysian atrophy gene was performed, and the CAG trinucleotide repeat numbers in this patient were 61/15. Gene analysis of the patient’s parents was not performed. The molecular mechanisms of the occurrence of sporadic cases have not been clarified.

SUMO-1 co-localized with mutant atrophin-1 with expanded polyglutamines accelerates intranuclear aggregation and cell death.

To investigate the implication of small ubiquitin-related modifier-1 (SUMO-1) in the formation of neuronal intranuclear inclusions in polyglutamine diseases, we examined the localization of SUMO-1 in dentatorubral-pallidoluysian atrophy (DRPLA) brain tissues and PC12 cells expressing truncated atrophin-1 with expanded poly-glutamine stretches. SUMO-1 was co-localized with neuronal intranuclear inclusions in DRPLA brain and the DRPLA model cells, which showed that the aggregates formed by expanded polyglutamine stretches were highly SUMOlylated. In addition, to examine the role of SUMO-1 in nuclear aggregate formation and cell death, either SUMO-1 or DeltaSUMO-1, which is a SUMOlylation defective mutant lacking the C-terminal motif, was co-transfected with atrophin-1 with expanded polyglutamine stretches. Co-transfection of DeltaSUMO-1 decreased number of the cells with nuclear aggregates and consequent apoptosis of PC12 cells, both of which were markedly enhanced by co-transfection of SUMO-1 with atrophin-1 with expanded polyglutamine stretches. These results suggest that SUMO-1 is implicated in the pathogenesis of DRPLA and accelerates aggregate formation and cell death.

Genotype-phenotype correlation in CAG-repeat diseases.

The expansion of a CAG repeat is a common causative gene mutation in several hereditary neurodegenerative disorders, including dentatorubral-pallidoluysian atrophy (DRPLA). Although, in DRPLA, it is revealed that the variety of clinical manifestations is related to the variable expansion of the CAG repeat, there are still many problems in the correlation between the symptoms and neuropathologic findings. Recent immunohistochemical studies have revealed that diffuse intranuclear accumulation of mutant proteins with expanded polyglutamine stretches is a significant pathology in DRPLA, and involves a wide range of the CNS regions far beyond the lesion distribution previously established by neuronal loss. This novel pathology may become a clue for elucidating molecular mechanisms of neuronal dysfunction and establishing clinicopathological correlations in CAG-repeat diseases.

Prevalence and ethnic differences of autosomal-dominant cerebellar ataxia in Singapore.

We report the prevalence and ethnic differences of autosomal-dominant cerebellar ataxia (ADCA) in Singapore. Amongst 204 patients with ataxia who underwent genetic testing for dentatorubral-pallidoluysian atrophy (DRPLA) and for spinocerebellar ataxias (SCA) 1, 2, 3, 6, 7, 8, 10 and 12, 58 (28.4%) patients from 36 families tested positive. SCA 3 was identified in 31 (53.4%) patients from 15 families, SCA 2 in 17 (29.3%) patients from 12 families and SCA 1 in four (6.9%) patients from four families. Other SCA subtypes were rare. SCA 2 was the only subtype identified amongst ethnic Malay and ethnic Indian families. The estimated prevalence of ADCA in Singaporean families was at least 1 : 27,000. Based on the history and ancestry of Singaporeans, our study supported a founder effect for specific SCA subtypes and the association of ethnicity-specific SCA subtypes. Our findings suggest that SCA 2 is relatively common amongst the Malay race and that priority testing for SCA 3 and SCA 2 for ethnic Chinese, and SCA 2 for ethnic Malay, may be cost effective and relevant for the region.

Oligodendrocytic polyglutamine pathology in dentatorubral-pallidoluysian atrophy.

White matter degeneration is one of the pathological conditions of dentatorubral-pallidoluysian atrophy. Autopsy brains exhibited a reduced number of glial cells in the lesions and an involvement of oligodendrocytes in nuclear inclusion formation, which previously has been recognized only as a pathological hallmark in neurons. Dentatorubral-pallidoluysian atrophy transgenic mice showed an increased number of affected glias with increasing age and with larger expansions of CAG repeats. These findings suggest that glial cells in dentatorubral-pallidoluysian atrophy also are involved in the polyglutamine pathogenesis.

Selective colocalization of transglutaminase-like activity in ubiquitinated intranuclear inclusions of hereditary dentatorubral-pallidoluysian atrophy

To investigate the role of transglutaminase (TG) in the pathophysiology of dentatorubral-pallidoluysian atrophy (DRPLA), the distributions of ubiquitin-positive neuronal intranuclear inclusions (Ub-NII) and TG activity were studied in three patients with DRPLA and four disease controls. In the cerebellar granule cells of DRPLA, 2.5–4.9% of neurons had Ub-NII, and 7.5–9.8% of them were TG positive. In the frontal cortex; however, the ratio of neurons with Ub-NII was relatively low compared with those in the cerebellar cortex, and no Ub-NII was TG positive. There was no distinct difference in the ratio of neurons with Ub-NII and their TG positivity between the cases with homozygous or heterozygous DRPLA patients. The selective and good colocalization of Ub-NII and TG in the cerebellar granule cells may reveal a role of TG in the neurodegenerative process in DRPLA.

Microarrays and polyglutamine disorders: reports from the Hereditary Disease Array Group.

Advances in molecular biology and genetics have allowed researchers to probe function and dysfunction at the level of the individual gene and/or protein. The integration of such information into an understanding of function has been a challenge facing all molecular geneticists and has contributed to the widening gap between molecular and systems scientists. In the neurosciences, this rift is especially dramatic. The ability to simultaneously monitor changes in the expression of thousands of genes using DNA microarrays has the potential to provide a global or ‘genomic’ view of brain function/ dysfunction. Two important barriers in the application of this technology to the study of neurological disease have been the availability of high-powered analytical approaches and appropriate genetic models. This issue of Human Molecular Genetics contains six contributions that approach these hurdles. These papers are centered on the application of DNA microarrays to survey alterations in gene expression associated with the expression of mutant polyglutamine proteins. A consortium headed by Dr Jim Olson of the Fred Hutchinson Cancer Research Center in Seattle and funded by the Hereditary Disease Foundation initiated this effort. Thus, this work is focused on the effects of expressing a mutant form of the Huntington disease (HD) gene product, huntingtin. Three papers, two by Luthi-Carter and colleagues (1,2) and one from Chan and co-workers (3), examine polyglutamineinduced changes in gene expression using several mouse models of HD. In the Luthi-Carter et al. contributions, mice expressing a truncated form of mutant huntingtin are examined. The first paper provides data that, in R6/2 mice (the often designated Bates mouse), a considerable number of genes have an altered pattern of expression and this pattern shows little sign of regional specificity (1). These are consistent with the previous pathological data indicating that this mouse model of HD shows little sign of the regional-specificity of disease as seen in patients. The second paper from the Luthi-Carter group compares gene expression changes between mouse models of dentatorubral–pallidoluysian atrophy and HD (2). At least in the cerebella of these mice, there was a considerable overlap in the genes showing altered gene expression. Thus, polyglutamine-induced changes in gene expression can be identified that are independent of the protein context in which the glutamine tract is located. Perhaps such context-independent genes reflect pathways that are common among the different polyglutamine

Difference in disease-free survival curve and regional distribution according to subtype of spinocerebellar ataxia: a study of 1,286 Japanese patients.

Expansions of trinucleotide repeats have been discovered in spinocerebellar ataxia (SCA) types 1, 2, 6, 7, 12, and 17, Machado-Joseph disease (MJD/SCA3), and dentatorubropallidoluysian atrophy (DRPLA). However, the frequency of familial SCA in Japan remains unclear. The number of trinucleotide repeats was determined for 1,286 patients. Three hundred and thirty families (523 cases) were autosomal dominant group (A), and 165 families were positive for family history but not autosomal dominant group (B), while the remaining 598 cases were the sporadic group (C). The frequency of SCA subtypes in autosomal dominant group was: 1) 5.5% for SCA1; 2) 2.4% for SCA2; 3) 27.6% for MJD/SCA3; 4) 25.5% for SCA6; 5) 0.3% for SCA17; and 6) 7.3% for DRPLA. Abnormal expansion of SCA12 was not detected. Another 31.5% of the patients in the autosomal dominant group had unknown genetic abnormalities. Within group B, SCA6 was the most prominent and within the sporadic group MJD/SCA3 and SCA6 were the most common subtypes observed. The disease-free survival curve of SCA6 was different from that of other SCAs and the mean age at onset for SCA6 was found to be later than that of the other types. Regional differences were observed in the relative rate of SCA subtypes. MJD/SCA3 appears more common in the Kanto and Kyushu districts of Japan, whereas SCA6 is most common in the Chugoku district. In order to establish an effective social welfare system for SCA patients, clinical course and regional differences in the prevalence of SCA subtypes must be taken into consideration.

Increased (CTG/CAG)(n) lengths in myotonic dystrophy type 1 and Machado-Joseph disease genes in idiopathic azoospermia patients.

An increase in CAG trinucleotide repeat length in the androgen receptor (AR) gene has been linked to idiopathic azoospermia. In order to test whether other (CAG/CTG)(n) loci are also affected, the (CAG/CTG)(n) frequency distribution at myotonic dystrophy type 1 (DM1), Machado-Joseph disease (MJD), dentatorubral-pallidoluysian atrophy (DRPLA) and spinocerebellar ataxia type 8 (SCA8) loci, in addition to the AR gene, was investigated in 48 azoospermia patients and 47 controls. The median CAG repeat length in the AR gene was significantly longer in azoospermia patients than in controls (23 versus 21, P < 0.001). Significant differences were also noted in the upper tails of trinucleotide repeat length distributions at both DM1 and MJD loci between the two populations. At the DM1 locus, alleles of more than 18 repeats were observed only in azoospermia patients, and not in controls (P = 0.014). At the MJD locus, the frequency of normal alleles (ANs) with 29 or more CAG repeats was also much higher in azoospermia patients (29.2 versus 7.4%; P = 0.0001). However, the repeat length distribution at DRPLA and SCA8 loci did not differ in the two groups. These data indicated that, at least in a subset of azoospermia patients, there was an increase in the number of trinucleotide repeats in some disease loci. Thus, it is noteworthy to evaluate whether offspring of these azoospermia patients, if born by assisted reproductive technologies, have an increased risk of trinucleotide repeat diseases.

Differentialdiagnose hereditärer Chorea-Syndrome

The clinical triad of hereditary chorea syndromes includes (1) choreatiform involuntary movement disorder, (2) psychiatric symptoms, and (3) cognitive impairment. The most frequent hereditary chorea syndrome is Huntington's disease (HD). There are several phenocopies of Huntington's disease, such as the Huntington's disease-like neurodegenerative disorders type 1 and type 2 (HDLD), benign hereditary chorea (BHC), dentato-rubro-pallido-Luysian atrophy (DRPLA), choreoacanthocytosis (CHAC), and McLeod syndrome (MLS). Huntington's disease is caused by an instable CAG trinucleotide expansion in the Huntington disease gene, and onset age and severity of symptoms depend on the number of CAG repeats. The physiological function of the gene product Huntingtin and the disease mechanisms are not fully elucidated yet. However, experimental data strongly suggest that induction of apoptosis through a caspase (cysteine aspartate-specific proteases)-dependent mechanism might be an important factor for the development of the striatal neurodegeneration. The HDLDs are more or less exact phenocopies of Huntington's disease. Two chromosomal localisations are described, and one responsible gene, Junctophilin-3, is identified. The BHC manifests as a pure chorea syndrome, without major psychiatric or cognitive impairment. The disease is located on chromosome 14, but the responsible gene has not yet been identified. Apart from the Huntington's disease-like phenotype, DRPLA may manifest as a spinocerebellar ataxia, a progressive myoclonus epilepsy, or mixed phenotypes. DRPLA is caused by instable CAG expansions in Atrophin-1, whose physiological functions are not yet known. CHAC and MLS belong to the so-called neuroacanthocytosis syndromes. CHAC is an autosomal-recessive disorder characterised by a progressive chorea syndrome, perioral dyskinesias and mutilations, and - less frequently - an akinetic-rigid extrapyramidal syndrome and seizures. The responsible gene is located on chromosome 9, encoding chorein, a protein implicated in intracellular cell sorting. MLS is an X-linked multi-system disorder with haematological, neuromuscular, and CNS involvement. Haematologically, MLS is characterised by absent expression of the Kx erythrocyte antigen, weak expression of Kell antigens, acanthocytosis, and a compensated haemolytic state. Asymptomatic males have elevated serum creatine kinase levels, and are prone to develop neurological symptoms. Neuromuscular manifestations include myopathy, sensory-motor axonal neuropathy, and cardiomyopathy. CNS manifestations comprise a choreatiform movement disorder, neuropsychiatric abnormalities, and - less frequently - generalised seizures. MLS is caused by mutations of the XK gene encoding the XK protein, a putative membrane transport protein containing the Kx erythrocyte antigen. The XK protein is linked to the Kell glycoprotein by a single disulfide bond, probably forming a functional complex. The Kell protein is a member of the metalloproteinase family, and the XK protein has functional similarities to the CED-8 protein in nematodes, in which it controls the timing of apoptosis. These data strongly suggest an important role of the XK-Kell complex in striatal physiology. The advances in the molecular biology of hereditary chorea syndromes offer the possibility for a direct genetic analysis of affected individuals, and presymptomatic testing for individuals at risk.

Time course of polyglutamine aggregate body formation and cell death: enhanced growth in nucleus and an interval for cell death.

Polyglutamine (polyQ) aggregate bodies are a hallmark of dentatorubral-pallidoluysian atrophy and related neurodegenerative disorders, although the relationship between aggregate body formation and cell death is not clear. We analyzed the kinetics of polyQ aggregate formation and the time intervals for cell death, tracking individual cells using fluorescence video microscopy, for the first time. Expanded polyQ tracts of atrophin-1 with or without nuclear localization signal (NLS) labeled with green fluorescent protein (GFP) were constructed, Q57NLS/GFP and Q56/GFP, respectively. All of the Q57NLS/GFP aggregate bodies were in nuclei, and all of the Q56/GFP aggregate bodies were in cytoplasm. Aggregates of Q56/GFP were larger than those of Q57NLS/GFP. Surprisingly, a kinetic analysis showed that the latter grew 5.37 times faster than the former. The time interval between transfection and cell death was shorter in Q57NLS/GFP, but the time between the end of the rapid growing phase of aggregation and the start of the cell death process did not show a significant difference. Aggregate growth was confirmed to correspond to the accumulated free polyQ by the time of starting aggregation. These findings suggest that aggregate body formation induced by expanded polyQ stretches is a self-limiting process and is enhanced by factor(s) in nuclei, whereas it is not tightly bound to the cell death process.

Trinucleotide repeats in 202 families with ataxia: a small expanded (CAG)n allele at the SCA17 locus.

Ten neurodegenerative disorders characterized by spinocerebellar ataxia (SCA) are known to be caused by trinucleotide repeat (TNR) expansions. However, in some instances the molecular diagnosis is considered indeterminate because of the overlap between normal and affected allele ranges. In addition, the mechanism that generates expanded alleles is not completely understood. To examine the clinical and molecular characteristics of a large group of Portuguese and Brazilian families with ataxia to improve knowledge of the molecular diagnosis of SCA. We have (1) assessed repeat sizes at all known TNR loci implicated in SCA; (2) determined frequency distributions of normal alleles and expansions; and (3) looked at genotype-phenotype correlations in 202 unrelated Portuguese and Brazilian patients with SCA. Molecular analysis of TNR expansions was performed using polymerase chain reaction amplification. Patients from 110 unrelated families with SCA showed TNR expansions at 1 of the loci studied. Dominantly transmitted cases had (CAG)(n) expansions at the Machado-Joseph disease gene (MJD1) (63%), at SCA2 (3%), the gene for dentatorubropallidoluysian atrophy (DRPLA) (2%), SCA6 (1%), or SCA7 (1%) loci, or (CTG)(n) expansions at the SCA8 (2%) gene, whereas (GAA)(n) expansions in the Freidreich ataxia gene (FRDA) were found in 64% of families with recessive ataxia. Isolated patients also had TNR expansions at the MJD1 (6%), SCA8 (6%), or FRDA (8%) genes; in addition, an expanded allele at the TATA-binding protein gene (TBP), with 43 CAGs, was present in a patient with ataxia and mental deterioration. Associations between frequencies of SCA2 and SCA6 and a frequency of large normal alleles were found in Portuguese and Brazilian individuals, respectively. Interestingly, no association between the frequencies of DRPLA and large normal alleles was found in the Portuguese group. Our results show that (1) a significant number of isolated cases of ataxia are due to TNR expansions; (2) expanded DRPLA alleles in Portuguese families may have evolved from an ancestral haplotype; and (3) small (CAG)(n) expansions at the TBP gene may cause SCA17.

Expanded polyglutamine stretches form an ‘aggresome’

To understand the pathogenetic mechanisms underlying polyglutamine (polyQ) diseases, we investigated the mechanisms of the formation of aggregate bodies containing expanded polyQ stretches, focusing on dentatorubral-pallidoluysian atrophy (DRPLA). We demonstrated that the expression of a truncated DRPLA protein containing expanded polyQ stretches in COS-7 cells resulted in the formation of perinuclear aggregate bodies that are co-localized with γ-tubulin, a protein marker for the microtubules-organizing center (MTOC). A collapsed vimentin network surrounded these aggregate bodies. Furthermore, disruption of the microtubules (MTs) with nocodazole resulted in the formation of small aggregate bodies that were scattered throughout the cytoplasm. These findings suggest that the truncated DRPLA proteins containing expanded polyQ stretches unfold and form small aggregate bodies in the cell periphery. These aggregates move on MTs to the MTOC, where they remain as distinct ‘aggresomes’.

Juvenile dentatorubral-pallidoluysian atrophy: new clinical features

Dentatorubral-pallidoluysian atrophy is a rare autosomal-dominant neurodegenerative disorder caused by an expansion of a CAG repeat in the atrophin-1 gene on chromosome 12. Dentatorubral-pallidoluysian atrophy is characterized clinically by prominent anticipation and a wide variety of symptoms that depend on age of onset and number of trinucleotide repeats. The juvenile type of dentatorubral-pallidoluysian atrophy, like Huntington’s disease, is most commonly inherited via paternal transmission of the gene and most frequently presents with early-onset progressive myoclonus epilepsy with mental retardation and ataxia. We present six affected individuals with dentatorubral-pallidoluysian atrophy from a black family living in North America. This pedigree includes two severe juvenile-onset cases, one of maternal transmission and the other of paternal transmission. Both cases of juvenile-onset disease presented with autistic features and seizures. Interestingly, cranial magnetic resonance imaging performed on the more affected child revealed only mild cerebellar atrophy. The present family expands the clinical description of juvenile-onset dentatorubral-pallidoluysian atrophy and emphasizes the importance of considering dentatorubral-pallidoluysian atrophy in children with progressive myoclonus epilepsy.

Spinocerebellar ataxia type 10: a disease caused by a large ATTCT repeat expansion.

Spinocerebellar ataxia type 10 (SCA 1 0) is an autosomal dominant disease characterized by ataxia and seizures. 1-3 It belongs to a group of diseases known as autosomal dominant cerebellar ataxias (ADCAs). To date, 16 ADCA loci, including SCA1,4SCA2,5-7 SCA3/Machado-Joseph disease (MJD),8 SCA4,9 SCAS, 10 SCA6, II SCA7,12 SCA8,13 SCAlO,2,3 SCAll,14 SCA12,15 SCAI3,16 SCA14,17 SCA16,17a SCA1717b,17c,17d and dentatorubral-pallidoluysian atrophy (DRPLA), 18,19 have been mapped to specific chromosomal regions. While mutations involved in SCA4, SCAS, SCA 11, SCA13, SCA14 and SCA16 have not been identified, six of these 14 ADCAs, including SCA1, SCA2, SCA3IMJD, SCA6, SCA 7, SCA 17 and DRPLA, have shown an expansion of a coding CAG trinucleotide repeat tract as the disease-causing mutation at the respective loci. In each of these diseases, the CAG repeat encodes a polyglutamine tract; therefore, an expansion of the CAG repeat gives rise to an elongation of the polyglutamine tract in the protein product. There is increasing evidence that the elongated polyglutamine tract leads to a gain of novel toxic function that causes the disease. 2o -29 One exception may be SCA6, in which the polyglutamine tract is located in the alpha-l A calcium channel subunit (CA CNA J A) gene, which shows a high level of expression in cerebellum. II The expansion size is 21-33 repeats, which would be within the normal range for other SCAs. Functional alterations of the P/Q type calcium channels in the cerebellum is a likely consequence although a gain of novel toxic function has also been postulated as the pathogenic mechanism of SCA6. In most ADCAs with polyglutarnine expansions, the age of disease onset becomes progressively earlier in successive generations with

Analysis of the Allele Polymorphism of (CTG) n and (CAG) n Triplet Repeats in Loci DM, DRPLA, and SCA1 in Several Populations of Russia

Polymorphism of highly polymorphic triplet repeats CTG of the 3"-untranslated region of the myotonin protein kinase gene and CAG of the genes associated with dentatorubral-pallidoluysian atrophy (DRPLA, or Hew River syndrome) and spinocerebellar ataxia type 1 (SCA1) was analyzed in several ethnic populations of Russia. A difference in allele spectra of the three genes was demonstrated for populations differing in ethnic origin.

Drosophila Atrophin Homolog Functions as a Transcriptional Corepressor in Multiple Developmental Processes

Dentatorubral-pallidoluysian atrophy is a progressive neurodegenerative disease caused by the expansion of a polyglutamine repeats within the Atrophin-1 protein. The in vivo function of Atrophin-1 is unknown. We have characterized a Drosophila gene encoding an Atrophin family protein. Analysis of mutant phenotypes indicates that Drosophila Atrophin is required in diverse developmental processes including early embryonic patterning. Drosophila Atrophin genetically interacts with the transcription repressor even-skipped and is required for its repressive function in vivo. Drosophila Atrophin directly binds to Even-skipped in vitro. Furthermore, both human Atrophin-1 and Drosophila Atrophin repress transcription in vivo when tethered to DNA, and poly-Q expansion in Atrophin-1 reduces this repressive activity. We propose that Atrophin proteins function as versatile transcriptional corepressors and discuss a model that deregulation of transcription may contribute to the pathogenesis of neurodegeneration.