Polyglutamine spinocerebellar ataxias — from genes to potential treatments

Paulson, Henry L.; Shakkottai, Vikram G.; Clark, H. Brent; Orr, Harry T.

doi:10.1038/nrn.2017.92

Cited by 299 publications

(302 citation statements)

References 162 publications

(159 reference statements)

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“…Ataxin is thought to equilibrate between CIC complexes and RNA-binding RBM17 complexes, which regulates transcription and RNA processing, notably splicing. In the case of SCA1, the polyQ extensions favor ataxin-RBM17 complexes over those with CIC, thereby competing with CIC containing complexes and altering gene transcription (Lim et al 2008;Paulson et al 2017).…”

Section: Polycistronic Regions: Overlapping Orfs On One Mrnamentioning

confidence: 99%

Recognition of the polycistronic nature of human genes is critical to understanding the genotype-phenotype relationship

et al. 2018

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Technological advances promise unprecedented opportunities for whole exome sequencing and proteomic analyses of populations. Currently, data from genome and exome sequencing or proteomic studies are searched against reference genome annotations. This provides the foundation for research and clinical screening for genetic causes of pathologies. However, current genome annotations substantially underestimate the proteomic information encoded within a gene. Numerous studies have now demonstrated the expression and function of alternative (mainly small, sometimes overlapping) ORFs within mature gene transcripts. This has important consequences for the correlation of phenotypes and genotypes. Most alternative ORFs are not yet annotated because of a lack of evidence, and this absence from databases precludes their detection by standard proteomic methods, such as mass spectrometry. Here, we demonstrate how current approaches tend to overlook alternative ORFs, hindering the discovery of new genetic drivers and fundamental research. We discuss available tools and techniques to improve identification of proteins from alternative ORFs and finally suggest a novel annotation system to permit a more complete representation of the transcriptomic and proteomic information contained within a gene. Given the crucial challenge of distinguishing functional ORFs from random ones, the suggested pipeline emphasizes both experimental data and conservation signatures. The addition of alternative ORFs in databases will render identification less serendipitous and advance the pace of research and genomic knowledge. This review highlights the urgent medical and research need to incorporate alternative ORFs in current genome annotations and thus permit their inclusion in hypotheses and models, which relate phenotypes and genotypes.

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Section: Polycistronic Regions: Overlapping Orfs On One Mrnamentioning

confidence: 99%

Recognition of the polycistronic nature of human genes is critical to understanding the genotype-phenotype relationship

et al. 2018

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“…The frequency of SCA1 in China is relatively rarer than that of MJD (with a frequency of 62.34%), accounting for only approximately 7.23% of all SCA patients; moreover, this frequency is quite different from that of SCA1 patients with European Caucasian ancestry (with a frequency of 9%–41%) . In addition, partly owing to differences in the size of the CAG repeat expansion, there is considerable variability in SCA1 neurological features, mainly including cerebellar ataxia, pyramidal symptoms and extrapyramidal symptoms, as well as eye movement disorders . In a series of European Caucasian ancestry studies evaluating eye movements in SCA1 patients, the authors found an even distribution of eye movement abnormalities, mainly encompassing saccade abnormalities, ophthalmoparesis and abnormal smooth pursuit .…”

Section: Discussionmentioning

confidence: 98%

(CAG)_n loci as genetic modifiers of age at onset in patients with spinocerebellar ataxia type 1 from mainland China

Wang¹,

Chen²,

Peng³

et al. 2019

Euro J of Neurology

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Background and purpose The expanded repeat length in ATXN1 negatively correlates with age at onset (AAO) of spinocerebellar ataxia type 1 (SCA1) but can explain only part of it, indicating that other factors affect AAO. Some studies have explored the influence of non‐causative CAG repeats on the AAO of SCA patients. However, studies on Chinese SCA1 patients regarding candidate modifier factors involved in the variability in AAO are rare. Methods In all, 152 Chinese SCA1 patients who were genotyped for ATXN1 and nine other (CAG)n‐containing genes were enrolled. Regression analysis was performed to determine the effect of the expanded allele of ATXN1 (linear and quadratic effects) on AAO. Then, different models were used to explore the modulatory effect of nine other (CAG)n‐containing genes. Results Our results verified the negative effect of the expanded allele in ATXN1 by regression analysis. Some (CAG)n‐containing genes including TBP, ATN1 and HTT modified AAO with variance ranging from 0.8% to 3.8% and tended to decrease or delay AAO. However, no modifier effects of ATXN2, ATXN3, CACNA1A, ATXN7, KCNN3, RAI1 and normal ATXN1 alleles in trans were detected. Conclusion By using interaction analyses, TBP, ATN1 and HTT were determined to have modifying effects. Our study revealed that differences in modulation may be due to ethnic and geographic diversity across different populations. Furthermore, the variability of AAO was not completely explained by the genetic modifiers examined here, suggesting that other genetic or environmental factors are involved in these diseases.

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“…Patients may also develop pyramidal, extrapyramidal signs, ophthalmoplegia and cognitive impairment in specific SCAs. Despite of the diverse number of pathogenic genes, the underlying pathogenic mechanism is proposed to involve the toxic polyglutamine protein [18]. Expansions in coding CAG [a form of trinucleotide repeat (TNR)] encoding for polyglutamine tracts account for 45% of the total population of autosomal dominant inherited ataxias.…”

Section: Introductionmentioning

confidence: 99%

DNA repair in trinucleotide repeat ataxias

et al. 2018

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The inherited cerebellar ataxias comprise of a genetic heterogeneous group of disorders. Pathogenic expansions of cytosine-adenine-guanine (CAG) encoding polyglutamine tracts account for the largest proportion of autosomal dominant cerebellar ataxias, while GAA expansion in the first introns of frataxin gene is the commonest cause of autosomal recessive cerebellar ataxias. Currently, there is no available treatment to alter the disease trajectory, with devastating consequences for affected individuals. Inter- and Intrafamily phenotypic variability suggest the existence of genetic modifiers, which may become targets amendable to treatment. Recent studies have demonstrated the importance of DNA repair pathways in modifying spinocerebellar ataxia with CAG repeat expansions. In this review, we discuss the mechanisms in which DNA repair pathways, epigenetics and other genetic factors may act as modifiers in cerebellar ataxias due to trinucleotide repeat expansions.

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Polyglutamine spinocerebellar ataxias — from genes to potential treatments

Cited by 299 publications

References 162 publications

Recognition of the polycistronic nature of human genes is critical to understanding the genotype-phenotype relationship

Recognition of the polycistronic nature of human genes is critical to understanding the genotype-phenotype relationship

(CAG)_n loci as genetic modifiers of age at onset in patients with spinocerebellar ataxia type 1 from mainland China

DNA repair in trinucleotide repeat ataxias

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Polyglutamine spinocerebellar ataxias — from genes to potential treatments

Cited by 299 publications

References 162 publications

Recognition of the polycistronic nature of human genes is critical to understanding the genotype-phenotype relationship

Recognition of the polycistronic nature of human genes is critical to understanding the genotype-phenotype relationship

(CAG)n loci as genetic modifiers of age at onset in patients with spinocerebellar ataxia type 1 from mainland China

DNA repair in trinucleotide repeat ataxias

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(CAG)_n loci as genetic modifiers of age at onset in patients with spinocerebellar ataxia type 1 from mainland China