Objective: To investigate the role of a hexanucleotide repeat within a SINE-VNTR-Alu (SVA) retrotransposon insertion in the TAF1 gene in modifying expressivity of X-linked dystonia-parkinsonism (XDP).

Background: XDP is a neurodegenerative movement disorder likely caused by an SVA retrotransposon insertion in TAF1 in all patients (1, 2). Nevertheless, XDP patients show remarkable phenotypic variability. Recently, a (CCCTCT)n repeat within the SVA insertion has been reported as an age-at-onset (AAO) modifier in XDP (3).

Method: By genotyping, we determined the number of (CCCTCT)n repeats (RN) in 355 XDP patients and associated it with: AAO (n=295), initial clinical manifestation (n=294), site of dystonia onset (n=238), disease severity (n=28), and cognitive function (n=15). The study participants belonged to 76 families, allowing us to assess the germline RN instability. Furthermore, we analyzed post-mortem brain samples from two affected individuals.

Results: RN showed significant inverse correlations with AAO and a positive correlation with disease severity and cognitive dysfunction. Importantly, AAO (and not the RN) was directly associated with whether dystonia or parkinsonism will manifest at onset. In comparison to patients affected by blepharospasm, RN was lower in individuals manifesting with mouth/tongue dystonia. RN was unstable across germline transmissions with an overall tendency to increase in length and exhibited somatic mosaicism in the brain.

Conclusion: Our work reveals that the hexanucleotide repeat within the SVA insertion acts as a genetic modifier of disease expressivity in XDP. Our findings suggest that the repeat expansion in XDP is a potentially druggable target using similar approaches as are currently being followed in the field of repeat expansion disorders.

References: 1. Rakovic A, Domingo A, Grütz K, et al. Genome editing in induced pluripotent stem cells rescues TAF1 levels in X-linked dystonia-parkinsonism. Mov Disord 2018;33. 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;172:897-909.e21. 3. 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. Proc Natl Acad Sci U S A 2017;114:E11020-E11028.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-hexanucleotide-repeat-within-a-sine-vntr-alu-retrotransposon-inserted-in-taf1-modifies-expressivity-of-x-linked-dystonia-parkinsonism/