3.073 Epigenetic Dna-Methylation in the Core Ataxin-2 Gene Promoter: Novel Physiological and Pathological Implications

Laffita, J.; Bauer, Peter; Kouri, Vesa‐Petteri; PeñaSerrano, L.; Roskams, Jane; Gotay, Dennis Almaguer; Santiago, Jesus; González-Zaldívar, Y.; Mederos, Luis Enrique Almaguer; Cuello-Almarales, Dany; Brown, Jay C.

doi:10.1016/s1353-8020(11)70809-4

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“…Since Elden and colleagues reported that a 27–33 CAG repeat expansion in the ATXN2 gene was associated with sporadic ALS in 2010 [43] , [47] , about two dozen studies have sought to verify this association [46] , [48] – [60] , investigate the mechanisms by which ALS may develop [61] , [62] , or investigate different clinical manifestations in ALS patients carrying CAG repeat expansions in the ATXN2 gene [61] – [64] . The initial study focused on the range 27–33 in the number of CAG repeats, and determined this range as an intermediate CAG (PolyQ) repeat using ROC curves.…”

Section: Resultsmentioning

confidence: 99%

“…To address this issue, we compared the CAG repeat range between ALS patients and controls based on the information from the 13 studies selected for inclusion in Figure 2 [46] , [48] – [60] . A high frequency of 27Q repeats was noticed in ALS patients, Parkinson's disease (PD) patients, and controls in Europe and North America ( Figure 2a ), but not in Chinese ALS patients or healthy controls ( Figure 2b ), where the peak of 27 CAG repeats in the ATXN 2 gene was essentially absent [58] , [59] .…”

Section: Resultsmentioning

confidence: 99%

“…High CAG repeat expansions (usually greater than 34 CAG repeat) in the ATXN2 gene [67] , transmitted in an autosomal dominant manner, is the cause of spinocerebellar ataxia type 2 (SCA2), a progressive neurodegenerative disease of the cerebellum, brain stem and spinal cord, with a somewhat higher incidence in Cuba than elsewhere [46] , [60] , [69] . The intermediate expansion of CAG repeats in SCA2 cases has also been reported [70] , [71] , and coincidence of ALS and SCA2 patients in the same family has been observed [72] , indicating a certain degree of overlap between SCA2 and ALS with CAG repeat expansion in the ATXN2 gene.…”

Section: Discussionmentioning

confidence: 99%

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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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