Objective: To assess the influence of SNP rs7969300 within ATXN2 locus on the age of onset in patients with Spinocerebellar Ataxia type 2.

Background: It is well known that the CAG repeat number in expanded ATXN2 alleles is the major genetic determinant of clinical severity in Spinocerebellar Ataxia type 2. However, there is huge variability in the clinical phenotype even for individuals sharing the same CAG repeat number, suggesting there are additional genetic factors modifying the clinical phenotype.

Method: Information on age of onset was obtained from 430 SCA2 patients belonging to 109 unique Cuban SCA2 families.The CAG repeat number at the ATXN2 locus was determined by PCR followed by polyacrilamide gel electrophoresis. Meanwhile, the SNP rs7969300 was assessed by qPCR using a TaqMan assay. Prediction of potential serine residues phosphorylation sites in the ataxin-2 protein was conducted using Netphos-3.1b server.

Results: A highly significant influence of expanded and normal ATXN2 alleles over age of onset was obtained, which accounted for 68.6% of the observed AO variability. The addition of SNP rs7969300 genotypes to the regression model improved the coefficient of determination (R2) in a 0.3%, while the inclusion of the interaction term between SNP rs7969300 genotypes and sex also improved it in a 0.5%. A significant difference was obtained for age of onset residuals across SNP rs7969300 genotypes for male but not female patients. It was predicted that serine residue in position 248 of ataxin-2 protein has a 99.5 probability of being a phosphorylation site.

Conclusion: Evidence is provided for a sex-specific effect of SNP rs7969300 on the age of onset of SCA2 in Cuban patients. Further functional studies would be valuable to establish the role of SNP rs7969300 in SCA2 physiopathology.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/sex-specific-effect-of-atxn2-rs7969300-polymorphism-on-age-at-onset-in-spinocerebellar-ataxia-type-2/