A non-synonymous SNP in SIRT6 predicts neurological severity in Friedreich ataxia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA827169 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description: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 FXN gene in part explains Inter-individual variability in severity of disease. The GAA repeat expansion leads to epigenetic silencing of FXN; therefore, variability in properties of epigenetic effector proteins could also regulate the severity of FRDA. In an exploratory analysis, DNA from 88 FRDA patients was analyzed to determine if any of 5 non-synonymous SNPs in HDACs/ SIRTs predicted FRDA disease severity. Results suggested the need for a full analysis (569 FRDA patients) at the rs352493 locus in SIRT6 (S46N SNP). Disease features were compared between patients with the common N46 SIRT6 variant and the less common S46 variant. Biochemical properties of SIRT6 were compared between S46 and N46. Linear regression of the exploratory cohort suggested a SNP (rs352493) in SIRT6 predicted neurologic severity. In follow up analysis, the genotype of SIRT6 at the locus rs352493 predicted disease features of FRDA. Patients with the S46 SIRT6 variant performed better on measures of neurological and visual function over time when compared to the more common N46 SIRT6 variant. S46 SIRT6 did not alter expression or enzymatic activity of SIRT6 or FXN however, S46 patients showed whole transcriptome differences compared to N46 patients, indicative of compensatory mechanisms against whole transcriptome changes seen in FRDA.
2022-10-04 | GSE200907 | GEO
Project description:Introduction: 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 FXN gene in part explains the interindividual variability in the severity of disease. The GAA repeat expansion leads to epigenetic silencing of FXN; therefore, variability in properties of epigenetic effector proteins could also regulate the severity of FRDA. Methods: In an exploratory analysis, DNA from 88 individuals with FRDA was analyzed to determine if any of five non-synonymous SNPs in HDACs/SIRTs predicted FRDA disease severity. Results suggested the need for a full analysis at the rs352493 locus in SIRT6 (p.Asn46Ser). In a cohort of 569 subjects with FRDA, disease features were compared between subjects homozygous for the common thymine SIRT6 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. Results: Linear regression in the exploratory cohort suggested that an SNP (rs352493) in SIRT6 correlated with neurological severity in FRDA. The follow-up analysis in a larger cohort agreed with the initial result that the genotype of SIRT6 at the locus rs352493 predicted the severity of disease features of FRDA. Those in the CT SIRT6 group performed better on measures of neurological and visual function over time than those in the more common TT SIRT6 group. The Asn to Ser amino acid change resulting from the SNP in SIRT6 did not alter the expression or enzymatic activity of SIRT6 or frataxin, but iPSC-derived neurons from people with FRDA in the CT SIRT6 group showed whole transcriptome differences compared to those in the TT SIRT6 group. Conclusion: People with FRDA in the CT SIRT6 group have less severe neurological and visual dysfunction than those in the TT SIRT6 group. Biochemical analyses indicate that the benefit conferred by T to C SNP in SIRT6 does not come from altered expression or enzymatic activity of SIRT6 or frataxin but is associated with changes in the transcriptome.
| S-EPMC9483148 | biostudies-literature
Project description:Background: Friedreich ataxia, an autosomal recessive neurodegenerative and cardiac disease, is caused by abnormally low levels of frataxin, an essential mitochondrial protein. All Friedreich ataxia patients carry a GAA/TTC repeat expansion in the first intron of the frataxin gene, either in the homozygous state or in compound heterozygosity with other loss-of-function mutations. The GAA expansion inhibits frataxin expression through a heterochromatin-mediated repression mechanism. Histone modifications that are characteristic of silenced genes in heterochromatic regions occur at expanded alleles in cells from Friedreich ataxia patients, including increased trimethylation of histone H3 at lysine 9 and hypoacetylation of histones H3 and H4. Methodology/Principal Findings: By chromatin immunoprecipitation, we detected the same heterochromatin marks in homozygous mice carrying a (GAA)230 repeat in the first intron of the mouse frataxin gene (KIKI mice). These animals have decreased frataxin levels and, by microarray analysis, show significant gene expression changes in several tissues. We treated KIKI mice with a novel histone deacetylase inhibitor, compound 106, which substantially increases frataxin mRNA levels in cells from Friedreich ataxia individuals. Treatment increased histone H3 and H4 acetylation in chromatin near the GAA repeat and restored wild-type frataxin levels in the nervous system and heart, as determined by quantitative RT-PCR and semiquantitative western blot analysis. No toxicity was observed. Furthermore, most of the differentially expressed genes in KIKI mice reverted towards wild-type levels. Conclusions/Significance: Lack of acute toxicity, normalization of frataxin levels and of the transcription profile changes resulting from frataxin deficiency provide strong support to a possible efficacy of this or related compounds in reverting the pathological process in Friedreich ataxia, a so far incurable neurodegenerative disease. Keywords: drug response
2008-03-08 | GSE10745 | GEO
Project description:We identified a synthetic siRNA (B11) that improves the growth of primary human fibroblasts derived from Friedreich ataxia (FA) patient. A control siRNA, in which one base pair of B11 is mutated (Mut1), was associated with a partial loss of phenotype. This experiment compares the transcriptome of primary FA fibroblasts transfected with B11 siRNA versus the transcriptome of FA cells transfected with Mut1.
2018-11-21 | E-MTAB-4699 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE13206: Human shSIRT6 TNF-alpha timecourse GSE13207: Mouse Sirt6-/- TNF-alpha timecourse GSE13208: Mouse Sirt6-/- tissues GSE13209: Mouse Sirt6-/- RelA+/- tissues Refer to individual Series
2010-06-24 | E-GEOD-13272 | biostudies-arrayexpress
Project description:We set out to investigate whether a histone deacetylase inhibitor (HDACi) would be effective in an in vitro model for the neurodegenerative disease Friedreich ataxia (FRDA) and to evaluate safety and surrogate markers of efficacy in a phase I clinical trial in patients. In the neuronal cell model, HDACi 109/RG2833 increases FXN mRNA levels and frataxin protein, with concomitant changes in the epigenetic state of the gene. Chromatin signatures indicate that histone H3 lysine 9 is a key residue for gene silencing through methylation and reactivation through acetylation, mediated by the HDACi. Drug treatment in FRDA patients demonstrated increased FXN mRNA and H3 lysine 9 acetylation in peripheral blood mononuclear cells. No safety issues were encountered.
2015-01-29 | GSE65399 | GEO
Project description:Microarray analysis of liver tissue from WT SIRT6 and conditional knockout of SIRT6 using albumin-Cre (SIRT6Co/Co ;Alb-Cre) at 2 and 8 months of age RNA was extracted from mouse liver tissue at 2 and 8 months of age. RNA from three pairs of WT SIRT6 and SIRT6Co/Co ;Alb-Cre mice was combined and hybridized to Affymetrix mouse gene 1.0 ST arrays.
2010-06-08 | E-GEOD-21965 | biostudies-arrayexpress
Project description:Dual targeting of brain region-specific kinases potentiates neurological rescue in Spinocerebellar ataxia type 1
| PRJNA635374 | ENA
Project description:Microarray analysis of liver tissue from WT SIRT6 and conditional knockout of SIRT6 using albumin-Cre (SIRT6Co/Co ;Alb-Cre) at 2 and 8 months of age
2010-05-28 | GSE21965 | GEO