TY - JOUR
T1 - Disease onset in X-linked dystonia-parkinsonism correlates with expansion of a hexameric repeat within an SVA retrotransposon in TAF1
AU - Bragg, D. Cristopher
AU - Mangkalaphiban, Kotchaphorn
AU - Vaine, Christine A.
AU - Kulkarni, Nichita J.
AU - Shin, David
AU - Yadav, Rachita
AU - Dhakal, Jyotsna
AU - Ton, Mai Linh
AU - Cheng, Anne
AU - Russo, Christopher T.
AU - Ang, Mark
AU - Acuña, Patrick
AU - Go, Criscely
AU - Franceour, Taylor N.
AU - Multhaupt-Buell, Trisha
AU - Ito, Naoto
AU - Müller, Ulrich
AU - Hendriks, William T.
AU - Breakefield, Xandra O.
AU - Sharma, Nutan
AU - Ozelius, Laurie J.
AU - Snyder, Solomon H.
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Dr. Winnie Xin (Massachusetts General Hospital, MGH) and Ms. Rosemary Barone (MGH) for assistance with quantification of hexameric repeat tract length in DNA samples. Funding for this study was provided by the MGH Collaborative Center for X-Linked Dystonia-Parkinsonism (D.C.B., N.S., and X.O.B.) and by NIH Grants 5P01NS087997 (to L.J.O., D.C.B., N.S., and X.O.B.) and R01NS102423 (to D.C.B. and L.J.O.).
PY - 2017/12/19
Y1 - 2017/12/19
N2 - 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 of TAF1. This unique insertion coincides with six additional noncoding sequence changes in TAF1, 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)n. The 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 in TAF1 expression.
AB - 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 of TAF1. This unique insertion coincides with six additional noncoding sequence changes in TAF1, 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)n. The 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 in TAF1 expression.
KW - DYT3
KW - Dystonia
KW - Parkinson's disease
KW - TAF1
KW - XDP
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U2 - 10.1073/pnas.1712526114
DO - 10.1073/pnas.1712526114
M3 - Article
C2 - 29229810
AN - SCOPUS:85038852805
SN - 0027-8424
VL - 114
SP - E11020-E11028
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 51
ER -