Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Jul;39(7):1145-1153.
doi: 10.1002/mds.29809. Epub 2024 Apr 14.

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

Joshua Laß  1 , Theresa Lüth  1 , Kathleen Schlüter  1 , Susen Schaake  1 , Björn-Hergen Laabs  2 , Christoph Much  1 , Roland Dominic Jamora  3 , Raymond L Rosales  4 , Gerard Saranza  5 , Cid Czarina E Diesta  6 , Christopher E Pearson  7 , Inke R König  2 , Norbert Brüggemann  1   8 , Christine Klein  1 , Ana Westenberger  1 , Joanne Trinh  1
Affiliations

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

Joshua Laß et al. Mov Disord. 2024 Jul.

Abstract

Background: X-Linked dystonia-parkinsonism (XDP) is an adult-onset neurodegenerative disorder characterized by rapidly progressive dystonia and parkinsonism. Mosaic Divergent Repeat Interruptions affecting motif Length and Sequence (mDRILS) were recently found within the TAF1 SVA repeat tract and were shown to associate with repeat stability and age at onset in XDP, specifically the AGGG [5'-SINE-VNTR-Alu(AGAGGG)2AGGG(AGAGGG)n] mDRILS.

Objective: This study aimed to investigate the stability of mDRILS frequencies and stability of (AGAGGG)n repeat length during transmission in parent-offspring pairs.

Methods: Fifty-six families (n = 130) were investigated for generational transmission of repeat length and mDRILS. The mDRILS stability of 16 individuals was assessed at two sampling points 1 year apart. DNA was sequenced with long-read technologies after long-range polymerase chain reaction amplification of the TAF1 SVA. Repeat number and mDRILS were detected with Noise-Cancelling Repeat Finder (NCRF).

Results: When comparing the repeat domain, 51 of 65 children had either contractions or expansions of the repeat length. The AGGG frequency remained stable across generations at 0.074 (IQR: 0.069-0.078) (z = -0.526; P = 0.599). However, the median AGGG frequency in children with an expansion (0.072 [IQR: 0.066-0.076]) was lower compared with children with retention or contraction (0.080 [IQR: 0.073-0.083]) (z = -0.007; P = 0.003). In a logistic regression model, the AGGG frequency predicted the outcome of either expansion or retention/contraction when including repeat number and sex as covariates (β = 80.7; z-score = 2.63; P = 0.0085). The AGGG frequency varied slightly over 1 year (0.070 [IQR: 0.063-0.080] to 0.073 [IQR: 0.069-0.078]).

Conclusions: Our results show that a higher AGGG frequency may stabilize repeats across generations. This highlights the importance of further investigating mDRILS as a disease-modifying factor with generational differences. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: XDP; long‐read sequencing; repeat interruptions.

PubMed Disclaimer

References

    1. Pauly MG, Ruiz Lopez M, Westenberger A, et al. Expanding data collection for the MDSGene database: X‐linked dystonia‐parkinsonism as use case example. Mov Disord 2020;35(11):1933–1938.
    1. Lee LV, Munoz EL, Tan KT, Reyes MT. Sex linked recessive dystonia parkinsonism of Panay, Philippines (XDP). Mol Pathol 2001;54(6):362–368.
    1. Domingo A, Westenberger A, Lee LV, et al. New insights into the genetics of X‐linked dystonia‐parkinsonism (XDP, DYT3). Eur J Hum Genet 2015;23(10):1334–1340.
    1. Westenberger A, Reyes CJ, Saranza G, et al. A hexanucleotide repeat modifies expressivity of X‐linked dystonia parkinsonism. Ann Neurol 2019;85(6):812–822.
    1. Bragg DC, Mangkalaphiban K, Vaine CA, et al. Disease onset in X‐linked dystonia‐parkinsonism correlates with expansion of a hexameric repeat within an SVA retrotransposon in TAF1. Proc Natl Acad Sci U S A 2017;114(51):E11020–E11028.

Substances

Supplementary concepts

LinkOut - more resources