Common origin of pure and interrupted repeat expansions in spinocerebellar ataxia type 2 (SCA2)

Ramos, Eliana Marisa; Martins, Sandra; Alonso, Isabel; Emmel, Vanessa Erichsen; Saraiva-Pereira, Maria Luiza; Jardim, Laura Bannach; Coutinho, Paula; Sequeiros, Jorge; Silveira, Isabel

doi:10.1002/ajmg.b.31013

Cited by 31 publications

(32 citation statements)

References 28 publications

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“…Two internal CAG repeat structure either with single or three CAA interruptions in sporadic ALS case series was interpreted as multiple mechanisms for ATXN2 repeat expansions [17]. We observed a trend of pure CAG tracts gaining and removal of CAA interruptions in successive generations as shown in case II-10 (CAG 23+8) versus III-6 (CAG 8+8+4+8), respectively, indicating that both expansions share the same ancestor as previously proposed [35], and that mutational mechanism driving the removal or gaining CAA interruptions might occur concurrently.…”

Section: Discussionsupporting

confidence: 79%

De Novo Mutations in Ataxin-2 Gene and ALS Risk

Laffita-Mesa¹,

Pupo

Sera

et al. 2013

PLoS ONE

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Pathogenic CAG repeat expansion in the ataxin-2 gene (ATXN2) is the genetic cause of spinocerebellar ataxia type 2 (SCA2). Recently, it has been associated with Parkinsonism and increased genetic risk for amyotrophic lateral sclerosis (ALS). Here we report the association of de novo mutations in ATXN2 with autosomal dominant ALS. These findings support our previous conjectures based on population studies on the role of large normal ATXN2 alleles as the source for new mutations being involved in neurodegenerative pathologies associated with CAG expansions. The de novo mutations expanded from ALS/SCA2 non-risk alleles as proven by meta-analysis method. The ALS risk was associated with SCA2 alleles as well as with intermediate CAG lengths in the ATXN2. Higher risk for ALS was associated with pathogenic CAG repeat as revealed by meta-analysis.

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Section: Discussionsupporting

confidence: 79%

De Novo Mutations in Ataxin-2 Gene and ALS Risk

Laffita-Mesa¹,

Pupo

Sera

et al. 2013

PLoS ONE

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“…The ATXN2 gene without CAA triplets, which stabilizes the CAG repeats [79], may produce ataxin-2 protein with longer PolyQ repeats which is more toxic to the host cells, compared to the ataxin-2 protein produced by the gene with the CAA triplet. This type of triplet is less common in longer CAG repeats in the ATXN2 gene in SCA2 patients [46], [69], [80], [81]. The CAA interruption may explain why the intermediate CAG repeat expansion in ATXN2 is associated with ALS, and does not generally produce a mild type of SCA2.…”

Section: Discussionmentioning

confidence: 98%

Intermediate CAG Repeat Expansion in the ATXN2 Gene Is a Unique Genetic Risk Factor for ALS−A Systematic Review and Meta-Analysis of Observational Studies

et al. 2014

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Amyotrophic lateral sclerosis (ALS) is a rare degenerative condition of the motor neurons. Over 10% of ALS cases are linked to monogenic mutations, with the remainder thought to be due to other risk factors, including environmental factors, genetic polymorphisms, and possibly gene-environmental interactions. We examined the association between ALS and an intermediate CAG repeat expansion in the ATXN2 gene using a meta-analytic approach. Observational studies were searched with relevant disease and gene terms from MEDLINE, EMBASE, and PsycINFO from January 2010 through to January 2014. All identified articles were screened using disease terms, gene terms, population information, and CAG repeat information according to PRISMA guidelines. The final list of 17 articles was further evaluated based on the study location, time period, and authors to exclude multiple usage of the same study populations: 13 relevant articles were retained for this study. The range 30–33 CAG repeats in the ATXN2 gene was most strongly associated with ALS. The meta-analysis revealed that the presence of an intermediate CAG repeat (30-33) in the ATXN2 gene was associated with an increased risk of ALS [odds ratio (OR) = 4.44, 95%CI: 2.91–6.76)] in Caucasian ALS patients. There was no significant difference in the association of this CAG intermediate repeat expansion in the ATXN2 gene between familial ALS cases (OR = 3.59, 1.58–8.17) and sporadic ALS cases (OR = 3.16, 1.88–5.32). These results indicate that the presence of intermediate CAG repeat expansion in the ATXN2 gene is a specific genetic risk factor for ALS, unlike monogenic mutations with an autosomal dominant transmission mode, which cause a more severe phenotype of ALS, with a higher prevalence in familial ALS.

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“…These studies demonstrate that a complex relationship exists between microsatellites and disease, that involves not only length but also sequence polymorphisms. Importantly, iMSs might represent a reservoir of mutable alleles that can expand in subsequent generations, as was shown for SCA2 [21] and myotonic dystrophy type 2 [22].…”

Section: Introductionmentioning

confidence: 91%

Microsatellite Interruptions Stabilize Primate Genomes and Exist as Population-Specific Single Nucleotide Polymorphisms within Individual Human Genomes

et al. 2014

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Interruptions of microsatellite sequences impact genome evolution and can alter disease manifestation. However, human polymorphism levels at interrupted microsatellites (iMSs) are not known at a genome-wide scale, and the pathways for gaining interruptions are poorly understood. Using the 1000 Genomes Phase-1 variant call set, we interrogated mono-, di-, tri-, and tetranucleotide repeats up to 10 units in length. We detected ∼26,000–40,000 iMSs within each of four human population groups (African, European, East Asian, and American). We identified population-specific iMSs within exonic regions, and discovered that known disease-associated iMSs contain alleles present at differing frequencies among the populations. By analyzing longer microsatellites in primate genomes, we demonstrate that single interruptions result in a genome-wide average two- to six-fold reduction in microsatellite mutability, as compared with perfect microsatellites. Centrally located interruptions lowered mutability dramatically, by two to three orders of magnitude. Using a biochemical approach, we tested directly whether the mutability of a specific iMS is lower because of decreased DNA polymerase strand slippage errors. Modeling the adenomatous polyposis coli tumor suppressor gene sequence, we observed that a single base substitution interruption reduced strand slippage error rates five- to 50-fold, relative to a perfect repeat, during synthesis by DNA polymerases α, β, or η. Computationally, we demonstrate that iMSs arise primarily by base substitution mutations within individual human genomes. Our biochemical survey of human DNA polymerase α, β, δ, κ, and η error rates within certain microsatellites suggests that interruptions are created most frequently by low fidelity polymerases. Our combined computational and biochemical results demonstrate that iMSs are abundant in human genomes and are sources of population-specific genetic variation that may affect genome stability. The genome-wide identification of iMSs in human populations presented here has important implications for current models describing the impact of microsatellite polymorphisms on gene expression.

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Common origin of pure and interrupted repeat expansions in spinocerebellar ataxia type 2 (SCA2)

Cited by 31 publications

References 28 publications

De Novo Mutations in Ataxin-2 Gene and ALS Risk

De Novo Mutations in Ataxin-2 Gene and ALS Risk

Intermediate CAG Repeat Expansion in the ATXN2 Gene Is a Unique Genetic Risk Factor for ALS−A Systematic Review and Meta-Analysis of Observational Studies

Microsatellite Interruptions Stabilize Primate Genomes and Exist as Population-Specific Single Nucleotide Polymorphisms within Individual Human Genomes

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