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Analysis of the Hexanucleotide Repeat Domain in the TAF1 SVA Retrotransposon in X-Linked Dystonia-Parkinsonism

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Genomic Structural Variants in Nervous System Disorders

Part of the book series: Neuromethods ((NM,volume 182))

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Abstract

X-linked dystonia-parkinsonism (XDP) is a neurodegenerative movement disorder endemic to the Philippines. The disease is caused by the antisense insertion of a SINE-VNTR-Alu (SVA)-type retrotransposon within an intron of the TAF1 gene. Within the SVA, there is a polymorphic hexanucleotide repeat domain, (CCCTCT)n, which varies between 30 and 55 repeats and correlates with age at disease onset. There has been evidence to suggest that various hexanucleotide lengths influence the transcriptional activity of TAF1. Here we describe the experimental methods used to investigate repeat expansions within the SVA of the TAF1 gene. Specifically, we describe fragment analysis, Southern blotting, and nanopore single-molecule sequencing. Our goal is to provide the reader with guidelines on how to perform the wet lab techniques and bioinformatic pipelines to detect repeat expansions.

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References

  1. Iafrate AJ, Feuk L, Rivera MN et al (2004) Detection of large-scale variation in the human genome. Nat Genet 36:949–951. https://doi.org/10.1038/ng1416

    Article  CAS  PubMed  Google Scholar 

  2. De Coster W, De Rijk P, De Roeck A et al (2019) Structural variants identified by Oxford Nanopore PromethION sequencing of the human genome. Genome Res 29:1178–1187. https://doi.org/10.1101/gr.244939.118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. De Coster W, Van Broeckhoven C (2019) Newest methods for detecting structural variations. Trends Biotechnol 37:973–982. https://doi.org/10.1016/j.tibtech.2019.02.003

    Article  CAS  PubMed  Google Scholar 

  4. Makino S, Kaji R, Ando S et al (2007) Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism. Am J Hum Genet 80:393–406. https://doi.org/10.1086/512129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Aneichyk T, Hendriks WT, Yadav R et al (2018) Dissecting the causal mechanism of X-linked dystonia-parkinsonism by integrating genome and transcriptome assembly a mendelian form of dystonia arises from altered splicing and intron retention within a general transcription factor. Dissecting the causal. Cell 172:897–909. https://doi.org/10.1016/j.cell.2018.02.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Rakovic A, Domingo A, Grütz K et al (2018) Genome editing in induced pluripotent stem cells rescues TAF1 levels in X-linked dystonia-parkinsonism. Mov Disord 33:1108–1118. https://doi.org/10.1002/mds.27441

    Article  CAS  PubMed  Google Scholar 

  7. Bragg DC, Mangkalaphiban K, Vaine CA et al (2017) Disease onset in X-linked dystonia-parkinsonism correlates with expansion of a hexameric repeat within an SVA retrotransposon in TAF1. Proc Natl Acad Sci 114:E11020–E11028. https://doi.org/10.1073/pnas.1712526114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Westenberger A, Reyes CJ, Saranza G et al (2019) A hexanucleotide repeat modifies expressivity of X-linked dystonia parkinsonism. Ann Neurol 85:812–822. https://doi.org/10.1002/ana.25488

    Article  CAS  PubMed  Google Scholar 

  9. Hagerman R, Hagerman P (2013) Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome. Lancet Neurol 12:786–798. https://doi.org/10.1016/S1474-4422(13)70125-X

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hall DA, Jennings D, Seibyl J et al (2010) FMR1 gene expansion and scans without evidence of dopaminergic deficits in parkinsonism patients. Parkinsonism Relat Disord 16:608–611. https://doi.org/10.1016/j.parkreldis.2010.07.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. DeJesus-Hernandez M, Mackenzie IR, Boeve BF et al (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72:245–256. https://doi.org/10.1016/j.neuron.2011.09.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Renton AE, Majounie E, Waite A et al (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72:257–268. https://doi.org/10.1016/j.neuron.2011.09.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Theuns J, Verstraeten A, Sleegers K et al (2014) Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease. Neurology 83:1906–1913. https://doi.org/10.1212/WNL.0000000000001012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ishiura H, Shibata S, Yoshimura J et al (2019) Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease. Nat Genet 51:1222–1232. https://doi.org/10.1038/s41588-019-0458-z

    Article  CAS  PubMed  Google Scholar 

  15. Sone J, Mitsuhashi S, Fujita A et al (2019) Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease. Nat Genet 51:1215–1221. https://doi.org/10.1038/s41588-019-0459-y

    Article  CAS  PubMed  Google Scholar 

  16. Deng J, Gu M, Miao Y et al (2019) Long-read sequencing identified repeat expansions in the 5′UTR of the NOTCH2NLC gene from Chinese patients with neuronal intranuclear inclusion disease. J Med Genet:758–764. https://doi.org/10.1136/jmedgenet-2019-106268

  17. Paulson H (2018) Repeat expansion diseases, 1st edn. Elsevier B.V.

    Google Scholar 

  18. Furtado S, Payami H, Lockhart PJ et al (2004) Profile of families with parkinsonism-predominant spinocerebellar ataxia type 2 (SCA2). Mov Disord 19:622–629. https://doi.org/10.1002/mds.20074

    Article  PubMed  Google Scholar 

  19. Furtado S, Farrer M, Tsuboi Y et al (2002) SCA-2 presenting as parkinsonism in an Alberta family: clinical, genetic, and PET findings. Neurology 59:1625–1627. https://doi.org/10.1212/01.WNL.0000035625.19871.DC

    Article  CAS  PubMed  Google Scholar 

  20. Lee LV, Rivera C, Teleg RA et al (2011) The unique phenomenology of sex-linked dystonia parkinsonism (XDP, DYT3, “Lubag”). Int J Neurosci 121(Suppl):3–11. https://doi.org/10.3109/00207454.2010.526728

    Article  PubMed  Google Scholar 

  21. Goto S, Lee LV, Munoz EL et al (2005) Functional anatomy of the basal ganglia in X-linked recessive dystonia-parkinsonism. Ann Neurol 58:7–17. https://doi.org/10.1002/ana.20513

    Article  PubMed  Google Scholar 

  22. Sako W, Morigaki R, Kaji R et al (2011) Identification and localization of a neuron-specific isoform of TAF1 in rat brain: implications for neuropathology of DYT3 dystonia. Neuroscience 189:100–107. https://doi.org/10.1016/j.neuroscience.2011.05.031

    Article  CAS  PubMed  Google Scholar 

  23. Hanssen H, Heldmann M, Prasuhn J et al (2018) Basal ganglia and cerebellar pathology in X-linked dystonia-parkinsonism. Brain 141:2995–3008. https://doi.org/10.1093/brain/awy222

    Article  PubMed  Google Scholar 

  24. Arasaratnam CJ, Singh-Bains MK, Waldvogel HJ, Faull RLM (2021) Neuroimaging and neuropathology studies of X-linked dystonia parkinsonism. Neurobiol Dis 148:105186. https://doi.org/10.1016/j.nbd.2020.105186

    Article  CAS  PubMed  Google Scholar 

  25. Cenina ARF, Jamora RDG, Ledesma LK et al (2014) Nonmotor features in sex-linked dystonia parkinsonism. Neurodegener Dis Manag 4:283–289. https://doi.org/10.2217/nmt.14.16

    Article  PubMed  Google Scholar 

  26. Reyes CJ, Laabs B, Schaake S, et al (2021) Brain regional differences in hexanucleotide repeat length in X-linked dystonia-parkinsonism using nanopore sequencing. Neurol Genet 7(4):e608. https://doi.org/10.1212/NXG.0000000000000608

    Google Scholar 

  27. Kawarai T, Pasco PMD, Teleg RA et al (2013) Application of long-range polymerase chain reaction in the diagnosis of X-linked dystonia-parkinsonism. Neurogenetics 14:167–169. https://doi.org/10.1007/s10048-013-0357-x

    Article  PubMed  Google Scholar 

  28. Gomes-Pereira M, Bidichandani SI, Monckton DG (2004) Analysis of unstable triplet repeats using small-pool polymerase chain reaction. Methods Mol Biol 277:61–76. https://doi.org/10.1385/1-59259-804-8:061

    Article  CAS  PubMed  Google Scholar 

  29. Midha MK, Wu M, Chiu K-P (2019) Long-read sequencing in deciphering human genetics to a greater depth. Hum Genet 138:1201–1215. https://doi.org/10.1007/s00439-019-02064-y

    Article  CAS  PubMed  Google Scholar 

  30. van Dijk EL, Jaszczyszyn Y, Naquin D, Thermes C (2018) The third revolution in sequencing technology. Trends Genet 34:666–681. https://doi.org/10.1016/j.tig.2018.05.008

    Article  CAS  PubMed  Google Scholar 

  31. Gilpatrick T, Lee I, Graham JE et al (2020) Targeted nanopore sequencing with Cas9-guided adapter ligation. Nat Biotechnol 38:433–438. https://doi.org/10.1038/s41587-020-0407-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Labun K, Montague TG, Krause M et al (2019) CHOPCHOP v3: expanding the CRISPR web toolbox beyond genome editing. Nucleic Acids Res 47:W171–W174. https://doi.org/10.1093/nar/gkz365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Li H (2018) Minimap2: pairwise alignment for nucleotide sequences. Bioinformatics 34:3094–3100. https://doi.org/10.1093/bioinformatics/bty191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Giesselmann P, Brändl B, Raimondeau E et al (2019) Analysis of short tandem repeat expansions and their methylation state with nanopore sequencing. Nat Biotechnol 37:1478–1481. https://doi.org/10.1038/s41587-019-0293-x

    Article  CAS  PubMed  Google Scholar 

  35. Harris RS, Cechova M, Makova KD (2019) Noise-cancelling repeat finder: uncovering tandem repeats in error-prone long-read sequencing data. Bioinformatics 35:4809–4811. https://doi.org/10.1093/bioinformatics/btz484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Institute of Neurogenetics, University of Lübeck, Lübeck, Germany

    Charles Jourdan Reyes, Theresa Lüth & Joanne Trinh

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  1. Charles Jourdan Reyes
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  2. Theresa Lüth
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  3. Joanne Trinh
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Correspondence to Joanne Trinh .

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Editors and Affiliations

  1. Queen Square Institute of Neurology, University College London, London, UK

    Christos Proukakis

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Reyes, C.J., Lüth, T., Trinh, J. (2022). Analysis of the Hexanucleotide Repeat Domain in the TAF1 SVA Retrotransposon in X-Linked Dystonia-Parkinsonism. In: Proukakis, C. (eds) Genomic Structural Variants in Nervous System Disorders. Neuromethods, vol 182. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-2357-2_8

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  • DOI: https://doi.org/10.1007/978-1-0716-2357-2_8

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  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-2356-5

  • Online ISBN: 978-1-0716-2357-2

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