Inherited polyglutamine spinocerebellar ataxias in South Africa

Smith, Danielle C.; Bryer, Alan; Watson, Lauren M.; Greenberg, L J

doi:10.7196/samj.5521

Cited by 22 publications

(27 citation statements)

References 16 publications

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“…SCA7 occurs at an unusually high prevalence in the South African population, the result of a founder effect in patients of Black African ethnic origin. 12 Consequently, South African SCA7 patients display a unique phenomenon-a SNP (rs3774729) within the causative gene, ataxin-7, is linked to the mutation in all patients studied to date, with approximately 43% of these individuals heterozygous for the polymorphism (genotype data publically available in the next build of dbSNP, B140, at https://www.ncbi.nlm.nih.gov/SNP/). 13 This SNP provides an ideal target for developing an allele-specific silencing therapy.…”

Section: Introductionmentioning

confidence: 99%

Allele-specific silencing of mutant Ataxin-7 in SCA7 patient-derived fibroblasts

et al. 2014

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Polyglutamine (polyQ) disorders are inherited neurodegenerative conditions defined by a common pathogenic CAG repeat expansion leading to a toxic gain-of-function of the mutant protein. Consequences of this toxicity include activation of heatshock proteins (HSPs), impairment of the ubiquitin-proteasome pathway and transcriptional dysregulation. Several studies in animal models have shown that reducing levels of toxic protein using small RNAs would be an ideal therapeutic approach for such disorders, including spinocerebellar ataxia-7 (SCA7). However, testing such RNA interference (RNAi) effectors in genetically appropriate patient cell lines with a disease-relevant phenotype has yet to be explored. Here, we have used primary adult dermal fibroblasts from SCA7 patients and controls to assess the endogenous allele-specific silencing of ataxin-7 by two distinct siRNAs. We further identified altered expression of two disease-relevant transcripts in SCA7 patient cells: a twofold increase in levels of the HSP DNAJA1 and a twofold decrease in levels of the de-ubiquitinating enzyme, UCHL1. After siRNA treatment, the expression of both genes was restored towards normal levels. To our knowledge, this is the first time that allelespecific silencing of mutant ataxin-7, targeting a common SNP, has been demonstrated in patient cells. These findings highlight the advantage of an allele-specific RNAi-based therapeutic approach, and indicate the value of primary patient-derived cells as useful models for mechanistic studies and for measuring efficacy of RNAi effectors on a patient-to-patient basis in the polyQ diseases.

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Section: Introductionmentioning

confidence: 99%

Allele-specific silencing of mutant Ataxin-7 in SCA7 patient-derived fibroblasts

et al. 2014

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“…An interesting case is the founder effect of SCA7 in South Africa, where this disease represents 26.6% of SCA diseases [84], a figure that is significantly higher than the 2% occurrence worldwide [78]. This figure increases again when considering the native African population, in whom SCA7 represents 59% of all SCA diseases, while SCA3 only represents 1% [84]. In fact, distribution of SCAs in South Africa as a whole, drastically differs from that elsewhere [78,84].…”

Section: Prevalence and Incidencementioning

confidence: 76%

“…This figure increases again when considering the native African population, in whom SCA7 represents 59% of all SCA diseases, while SCA3 only represents 1% [84]. In fact, distribution of SCAs in South Africa as a whole, drastically differs from that elsewhere [78,84].…”

Section: Prevalence and Incidencementioning

confidence: 82%

“…With regards to SCA3, the prevalence is at its highest in Brazil (69% of SCA cases), Portugal (58%) and China (49%) and relatively low in USA (21%), India (3%) and Italy (1%) [77,[79][80][81][82][83]. An interesting case is the founder effect of SCA7 in South Africa, where this disease represents 26.6% of SCA diseases [84], a figure that is significantly higher than the 2% occurrence worldwide [78]. This figure increases again when considering the native African population, in whom SCA7 represents 59% of all SCA diseases, while SCA3 only represents 1% [84].…”

Section: Prevalence and Incidencementioning

confidence: 99%

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Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

McIntosh¹,

Htut²,

Fletcher³

et al. 2017

J Genet Syndr Gene Ther

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Spinocerebellar ataxias are a large group of heterogeneous diseases that all involve selective neuronal degeneration and accompanied cerebellar ataxia. These diseases can be further broken down into discrete groups according to their underlying molecular genetic cause. The most common are the polyglutamine ataxias, of which there are six; Spinocerebellar ataxia type 1, 2, 3, 6, 7 and 17. These diseases are characterised by a pathological expanded cytosine-adenine-guanine (CAG) repeat sequence, in the protein coding region of a given gene. Common clinical features include lack of coordination and gait ataxia, speech and swallowing difficulties, as well as impaired hand and motor functions. The polyglutamine spinocerebellar ataxias are typically late onset diseases that are progressive in nature and often lead to premature death, for which there is currently no known cure or effective treatment strategy. Although caused by the same molecular mechanism, the causative gene and associated protein differ for each disease. The exact mechanism by which disease pathogenesis is caused remains elusive. However, the variable (CAG) n repeats are codons that may be translated to an expanded glutamine tract, leading to conformational changes in the protein, giving it a toxic gain of function. Several pathogenic pathways have been implicated in polyglutamine spinocerebellar ataxia diseases, such as the hallmark feature of neuronal nuclear inclusions, protein misfolding and aggregation, as well as transcriptional dysregulation. These pathways are attractive avenues for potential therapeutic interventions, as the potential to treat more than one disease exists. Research is ongoing, and several promising therapies are currently underway in an attempt to provide relief for this devastating class of diseases.. However, mutations can arise de novo, through errors in DNA replication such that two genetically healthy parents can give rise to an affected child.There are currently six characterised polyQ SCAs (1, 2, 3, 6, 7 and 17) (Table 1), and together with three other diseases, namely Huntington's disease, spinal and bulbar muscular atrophy and dentatorubropallidoluysian atrophy (DRPLA), form a larger category of polyQ diseases [7][8][9][10]. Th ere is little relief for individuals suffering from polyQ SCA disorders, with symptomatic treatments the only available option. Long term pharmacological treatment, although admirable, tends to fall short in an effective management strategy, as unwanted complications and low drug efficacy still exist. In addition, none of these diseases have any treatments that slow the progression of the disease; leaving affected individuals with the daunting reality that time may be a severe limiting factor. Several experimental approaches are currently being assessed to overcome these difficulties. This review will focus on the clinical and molecular features of polyQ SCA diseases (which will be referred to as SCA diseases), as well as highlight several promising and emerging therapeutic strategies...

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“…13 The development of effective therapies for a group of genetic conditions known as the polyglutamine (polyQ) diseases is particularly relevant to SA populations where, for example, the frequencies of spinocerebellar ataxia type 1 (SCA1) and type 7 (SCA7) are among the highest in the world. 14 To date, our research has been primarily focused on the study of the SCA7 protein in transfected neuronal cell lines and transgenic mouse models. 15,16 A unique clinical feature of this condition is loss of vision associated with retinal degeneration (in particular the macula), the aetiology of which is unknown.…”

Section: Ips Cells and Disease-in-the-dish Modelsmentioning

confidence: 99%

A New Class of Stem Cells in South Africa: Introducing Induced Pluripotent Stem cells (iPS cells)

2012

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Inherited polyglutamine spinocerebellar ataxias in South Africa

Cited by 22 publications

References 16 publications

Allele-specific silencing of mutant Ataxin-7 in SCA7 patient-derived fibroblasts

Allele-specific silencing of mutant Ataxin-7 in SCA7 patient-derived fibroblasts

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

A New Class of Stem Cells in South Africa: Introducing Induced Pluripotent Stem cells (iPS cells)

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