Acta Neuropathologica Communications (Apr 2022)

Tissue-specific and repeat length-dependent somatic instability of the X-linked dystonia parkinsonism-associated CCCTCT repeat

  • Lindsey N. Campion,
  • Alan Meijia Maza,
  • Rachita Yadav,
  • Ellen B. Penney,
  • Micaela G. Murcar,
  • Kevin Correia,
  • Tammy Gillis,
  • Cara Fernandez-Cerado,
  • M. Salvie Velasco-Andrada,
  • G. Paul Legarda,
  • Niecy G. Ganza-Bautista,
  • J. Benedict B. Lagarde,
  • Patrick J. Acuña,
  • Trisha Multhaupt-Buell,
  • Gabrielle Aldykiewicz,
  • Melanie L. Supnet,
  • Jan K. De Guzman,
  • Criscely Go,
  • Nutan Sharma,
  • Edwin L. Munoz,
  • Mark C. Ang,
  • Cid Czarina E. Diesta,
  • D. Cristopher Bragg,
  • Laurie J. Ozelius,
  • Vanessa C. Wheeler

DOI
https://doi.org/10.1186/s40478-022-01349-0
Journal volume & issue
Vol. 10, no. 1
pp. 1 – 16

Abstract

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Abstract X-linked dystonia-parkinsonism (XDP) is a progressive adult-onset neurodegenerative disorder caused by insertion of a SINE-VNTR-Alu (SVA) retrotransposon in the TAF1 gene. The SVA retrotransposon contains a CCCTCT hexameric repeat tract of variable length, whose length is inversely correlated with age at onset. This places XDP in a broader class of repeat expansion diseases, characterized by the instability of their causative repeat mutations. Here, we observe similar inverse correlations between CCCTCT repeat length with age at onset and age at death and no obvious correlation with disease duration. To gain insight into repeat instability in XDP we performed comprehensive quantitative analyses of somatic instability of the XDP CCCTCT repeat in blood and in seventeen brain regions from affected males. Our findings reveal repeat length-dependent and expansion-based instability of the XDP CCCTCT repeat, with greater levels of expansion in brain than in blood. The brain exhibits regional-specific patterns of instability that are broadly similar across individuals, with cerebellum exhibiting low instability and cortical regions exhibiting relatively high instability. The spectrum of somatic instability in the brain includes a high proportion of moderate repeat length changes of up to 5 repeats, as well as expansions of ~ 20- > 100 repeats and contractions of ~ 20–40 repeats at lower frequencies. Comparison with HTT CAG repeat instability in postmortem Huntington’s disease brains reveals similar brain region-specific profiles, indicating common trans-acting factors that contribute to the instability of both repeats. Analyses in XDP brains of expansion of a different SVA-associated CCCTCT located in the LIPG gene, and not known to be disease-associated, reveals repeat length-dependent expansion at overall lower levels relative to the XDP CCCTCT repeat, suggesting that expansion propensity may be modified by local chromatin structure. Together, the data support a role for repeat length-dependent somatic expansion in the process(es) driving the onset of XDP and prompt further investigation into repeat dynamics and the relationship to disease.