AUTHOR=Rodden Layne N. , Rummey Christian , Dong Yi Na , Lagedrost Sarah , Regner Sean , Brocht Alicia , Bushara Khalaf , Delatycki Martin B. , Gomez Christopher M. , Mathews Katherine , Murray Sarah , Perlman Susan , Ravina Bernard , Subramony S. H. , Wilmot George , Zesiewicz Theresa , Bolotta Alessandra , Domissy Alain , Jespersen Christine , Ji Baohu , Soragni Elisabetta , Gottesfeld Joel M. , Lynch David R. 

TITLE=A non-synonymous single nucleotide polymorphism in SIRT6 predicts neurological severity in Friedreich ataxia

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=9

YEAR=2022

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2022.933788

DOI=10.3389/fmolb.2022.933788

ISSN=2296-889X

ABSTRACT=<p><bold>Introduction:</bold> Friedreich ataxia (FRDA) is a recessive neurodegenerative disease characterized by progressive ataxia, dyscoordination, and loss of vision. The variable length of the pathogenic GAA triplet repeat expansion in the <italic>FXN</italic> gene in part explains the interindividual variability in the severity of disease. The GAA repeat expansion leads to epigenetic silencing of <italic>FXN;</italic> therefore, variability in properties of epigenetic effector proteins could also regulate the severity of FRDA.</p><p><bold>Methods:</bold> In an exploratory analysis, DNA from 88 individuals with FRDA was analyzed to determine if any of five non-synonymous SNPs in <italic>HDAC</italic>s/<italic>SIRT</italic>s predicted FRDA disease severity. Results suggested the need for a full analysis at the rs352493 locus in <italic>SIRT6</italic> (<italic>p</italic>.Asn46Ser). In a cohort of 569 subjects with FRDA, disease features were compared between subjects homozygous for the common thymine <italic>SIRT6</italic> variant (TT) and those with the less common cytosine variant on one allele and thymine on the other (CT). The biochemical properties of both variants of SIRT6 were analyzed and compared.</p><p><bold>Results:</bold> Linear regression in the exploratory cohort suggested that an SNP (rs352493) in <italic>SIRT6</italic> correlated with neurological severity in FRDA. The follow-up analysis in a larger cohort agreed with the initial result that the genotype of <italic>SIRT6</italic> at the locus rs352493 predicted the severity of disease features of FRDA. Those in the CT <italic>SIRT6</italic> group performed better on measures of neurological and visual function over time than those in the more common TT <italic>SIRT6</italic> group. The Asn to Ser amino acid change resulting from the SNP in <italic>SIRT6</italic> did not alter the expression or enzymatic activity of SIRT6 or frataxin, but iPSC-derived neurons from people with FRDA in the CT <italic>SIRT6</italic> group showed whole transcriptome differences compared to those in the TT <italic>SIRT6</italic> group.</p><p><bold>Conclusion:</bold> People with FRDA in the CT <italic>SIRT6</italic> group have less severe neurological and visual dysfunction than those in the TT <italic>SIRT6</italic> group. Biochemical analyses indicate that the benefit conferred by T to C SNP in <italic>SIRT6</italic> does not come from altered expression or enzymatic activity of SIRT6 or frataxin but is associated with changes in the transcriptome.</p>