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Stability of Mosaic Divergent Repeat Interruptions in X-Linked Dystonia-Parkinsonism

Joshua Laß1, Theresa Lüth1, Kathleen Schlüter1

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

Movement Disorders : Official Journal of the Movement Disorder Society
|April 15, 2024
PubMed
Abstract

Insights

Mosaic Divergent Repeat Interruptions affecting motif Length and Sequence (mDRILS) in X-Linked dystonia-parkinsonism (XDP) show generational stability. Higher AGGG frequencies may stabilize TAF1 SVA repeats, suggesting mDRILS as a potential disease modifier.

Area of Science:

  • Genetics
  • Neurodegenerative Disorders
  • Molecular Biology

Background:

  • X-Linked dystonia-parkinsonism (XDP) is an adult-onset neurodegenerative disorder.
  • Mosaic Divergent Repeat Interruptions affecting motif Length and Sequence (mDRILS) in the TAF1 SVA repeat tract are associated with XDP.
  • Specific AGGG [5'-SINE-VNTR-Alu(AGAGGG)2AGGG(AGAGGG)n] mDRILS influence repeat stability and age at onset.

Purpose of the Study:

  • To investigate the stability of mDRILS frequencies across generations.
  • To assess the stability of (AGAGGG)n repeat length during parent-offspring transmission in XDP.
  • To explore the relationship between AGGG frequency and repeat length changes.

Main Methods:

  • Analysis of 56 families (130 individuals) for generational transmission of TAF1 SVA repeat length and mDRILS.
  • Long-read DNA sequencing of TAF1 SVA after long-range PCR amplification.
  • Detection of repeat number and mDRILS using Noise-Cancelling Repeat Finder (NCRF).

Main Results:

  • Repeat length contractions or expansions were observed in 51 of 65 children.
  • AGGG frequency remained stable across generations (median 0.074), but was lower in children with expansions compared to those with retention/contraction.
  • AGGG frequency significantly predicted expansion or retention/contraction outcomes in a logistic regression model.

Conclusions:

  • Higher AGGG frequencies may contribute to repeat stabilization across generations in XDP.
  • mDRILS represent a potential disease-modifying factor with significant generational implications.
  • Further research into mDRILS is crucial for understanding XDP pathogenesis.
Keywords:
XDPlong‐read sequencingrepeat interruptions

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