July 7, 2019  |  

Disease onset in X-linked dystonia-parkinsonism correlates with expansion of a hexameric repeat within an SVA retrotransposon in TAF1.

Authors: Bragg, D Cristopher and Mangkalaphiban, Kotchaphorn and Vaine, Christine A and Kulkarni, Nichita J and Shin, David and Yadav, Rachita and Dhakal, Jyotsna and Ton, Mai-Linh and Cheng, Anne and Russo, Christopher T and Ang, Mark and Acuña, Patrick and Go, Criscely and Franceour, Taylor N and Multhaupt-Buell, Trisha and Ito, Naoto and Müller, Ulrich and Hendriks, William T and Breakefield, Xandra O and Sharma, Nutan and Ozelius, Laurie J

X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease associated with an antisense insertion of a SINE-VNTR-Alu (SVA)-type retrotransposon within an intron ofTAF1This unique insertion coincides with six additional noncoding sequence changes inTAF1, the gene that encodes TATA-binding protein-associated factor-1, which appear to be inherited together as an identical haplotype in all reported cases. Here we examined the sequence of this SVA in XDP patients (n= 140) and detected polymorphic variation in the length of a hexanucleotide repeat domain, (CCCTCT)nThe number of repeats in these cases ranged from 35 to 52 and showed a highly significant inverse correlation with age at disease onset. Because other SVAs exhibit intrinsic promoter activity that depends in part on the hexameric domain, we assayed the transcriptional regulatory effects of varying hexameric lengths found in the unique XDP SVA retrotransposon using luciferase reporter constructs. When inserted sense or antisense to the luciferase reading frame, the XDP variants repressed or enhanced transcription, respectively, to an extent that appeared to vary with length of the hexamer. Further in silico analysis of this SVA sequence revealed multiple motifs predicted to form G-quadruplexes, with the greatest potential detected for the hexameric repeat domain. These data directly link sequence variation within the XDP-specific SVA sequence to phenotypic variability in clinical disease manifestation and provide insight into potential mechanisms by which this intronic retroelement may induce transcriptional interference inTAF1expression. Copyright © 2017 the Author(s). Published by PNAS.

Journal: Proceedings of the National Academy of Sciences of the United States of America
DOI: 10.1073/pnas.1712526114
Year: 2017

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