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.
Competing Interest Statement
V.C.W. is a scientific advisory board member of Triplet Therapeutics Inc., a company developing new therapeutic approaches to address triplet repeat disorders such Huntington disease and Myotonic Dystrophy. Her financial interests in Triplet Therapeutics were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. She is a scientific advisory board member of LoQus23 Therapeutics, Ltd and has provided paid consulting services to Alnylam, Inc., Acadia Pharmaceuticals and Biogen, Inc. She has also received research support from Pfizer Inc. L.J.O. receives royalties from Athena Diagnostics.
List of abbreviations
- XDP
- X-linked dystonia-parkinsonism
- SVA
- SINE-VNTR-Alu
- HD
- Huntington’s disease
- TAF1
- TATA-binding-protein (TBP)-associated factor-1
- TBP
- TATA-binding-protein
- LIPG
- Lipase G, Endothelial Type
- MSNs
- Medium-spiny neurons
- AAO
- Age at Onset
- AAD
- age at death
- GWAS
- genome-wide association
- IRBs
- MGH
- Massachusetts General Hospital
- IRB
- Institutional Review Board
- gDNA
- Genomic DNA
- CCXDP
- Collaborative Center for XDP
- DIG
- digoxygenin
- BA9
- frontal cortex Brodmann area 9
- SbN
- substantia nigra
- ION
- inferior olivary nucleus
- RN
- red nucleus
- DCN
- deep cerebellar nuclei
- STh
- subthalamic nucleus
- SP-PCR
- small pool-PCR
- HTT
- huntingtin
- MSH3
- MutS homolog
- 3: PMS2
- PMS1 homolog2, Mistmatch repair system component
- SCA1
- Spinocerebellar ataxia type 1