Objective: To investigate the impact of the hexanucleotide repeat within the X-linked dystonia-parkinsonism-associated haplotype on endogenous TAF1expression.

Background: X-linked dystonia-parkinsonism (XDP) is a severe neurodegenerative movement disorder presenting with adult-onset dystonia and/or parkinsonism.[1] One of the changes within the XDP-associated haplotype, a SINE-VNTR-Alu (SVA) retrotransposon insertion in intron 32 of TAF1, has been shown to functionally affect the expression of this gene.[2],[3] Namely, TAF1 transcripts are consistently downregulated in samples from XDP patients in comparison to healthy controls in gene-level and high-throughput experiments[4], and TAF1 mRNA reduction is a tractable molecular phenotype of XDP that can be rescued by excision of the SVA insertion[2],[3]. Recently, a (CCCTCT)n repeat within the SVA insertion has been reported as an age-at-onset (AAO) modifier in XDP.[5] However, it has not been shown whether the length of the repeat correlates with the expression of TAF1.

Method: Blood-derived RNAs of 31 XDP patients were transcribed into cDNAs. Expression of TAF1 was investigated via real-time quantitative PCR (qPCR) in triplicates and normalized to the expression of GAPDH and YWHAZ. The effect of the repeat number (RN) on TAF1 expression was analyzed by linear regression models.

Results: The expression of TAF1 normalized to GAPDH, YWHAZ, or both reference genes correlated negatively with increasing RN (R2: 0.3255, 0.2386, and 0.3279, respectively; all p<0.005).

Conclusion: Endogenous levels of TAF1 mRNA in the blood of XDP patients are reduced in an RN-dependent fashion. Thus, it seems likely, that the hexanucleotide repeat within the SVA is causing the decreased expression of TAF1 observed in XDP. The exact mechanism by which the hexameric repeat modifies TAF1 expression warrants further investigation.

References: [1] Lee L V., Rivera C, Teleg RA, et al. The unique phenomenology of sex-linked dystonia parkinsonism (XDP, DYT3, “Lubag”). International Journal of Neuroscience. 2011. doi:10.3109/00207454.2010.526728. [2] Aneichyk T, Hendriks WT, Yadav R, et al. Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly. Cell. 2018. doi:10.1016/j.cell.2018.02.011. [3] Rakovic A, Domingo A, Grütz K, et al. Genome editing in induced pluripotent stem cells rescues TAF1 levels in X-linked dystonia-parkinsonism. Movement disorders : official journal of the Movement Disorder Society. 2018;33(7):1108-1118. doi:10.1002/mds.27441. [4] Domingo A, Amar D, Grütz K, et al. Evidence of TAF1 dysfunction in peripheral models of X-linked dystonia-parkinsonism. Cellular and molecular life sciences : CMLS. 2016;73(16):3205-3215. doi:10.1007/s00018-016-2159-4. [5] Bragg DC, Mangkalaphiban K, Vaine CA, et al. Disease onset in X-linked dystonia-parkinsonism correlates with expansion of a hexameric repeat within an SVA retrotransposon in TAF1. Proceedings of the National Academy of Sciences. 2017. doi:10.1073/pnas.1712526114.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/is-the-gene-expression-of-taf1-modified-by-the-x-linked-dystonia-parkinsonism-associated-hexanucleotide-repeat/