Objective: To characterize genetics and epigenetics factors contributing to the origin and accounting to the Cuban SCA2 phenotype variability.

Background: CAG repeat expansions in ATXN2 gene cause SCA2 and contribute to Parkinson disease, ALS and other neurodegenerative diseases. Five recurrent questions are central in the study connected to ATXN2. 1) How pathological ATXN2 CAG repeats expansions originates in human populations? 2) What about regulatory mechanism controlling ATXN2 gene expression. 3) What is the ATXN2 physiological function. 4) Which are ATXN2 pathological mechanisms? 5) What factors account in the phenotype variability? Here we were focused on questions 1, 2 and 5.

Method: We developed genetic investigations using different approaches in the Cuban SCA2 population and ethnically matched controls (3000 chromosomes). We also investigated different families affected also by ALS but with CAG expansions in ATXN2.

Results: Here we present the widest characterization of genetic polymorphisms associated with ATXN2 CAG expansion in both affected and healthy population. We found large normal alleles associated with the highest SCA2 frequency (r2=0.841, p<0.000). Large normal alleles shown to be unstable in somatic and intergenerational transmissions(X2=59.80, p<0.0000), and we confirmed jumps from normal to pathological CAG repeats expansions associated either with SCA2 or ALS. Mutagenic mechanism was supported by haplotype and CAG sequence studies showing predisposing haplotype leading to loss of the CAA trip-let repeat interruption in the ATXN2. The observations lead us to define the ATXN2 pre-mutational CAG repeat expansion range from 25-31CAG. We developed molecular methods which enabled to identify epigenetic DNA methylation modifying the SCA2 age at onset (? 2511.59, p<0.0007). Poly-Q load presented as somatic mosaicism is also presented as potential modifying factor of age at onset and SCA2 disease.

Conclusion: Our results explained the connection between the frequency of SCA2 and normal alleles with increased CAG stretches lacking of CAA interruptions and with similar SCA2-SNP haplotype. DNA methylation is an intrinsic ATXN2 factor influencing gene expression and modifying SCA2 phenotype.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/ataxin-2-gene-in-the-cuban-population-mutagenesis-and-epigenetic-dna-methylation-disease-influencing-phenotype/