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

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.

Clinical implications of somatic allele expansion in female FMR1 premutation carriers

“…The presence of expansion could be a further modulator of this effect within the nervous system. Importantly, given what is seen in a mouse model of the FXDs 44 , and in patients with other repeat expansion diseases 45 , 46 , the degree of expansion may be higher in the brain compared to peripheral blood from which this study’s samples were obtained. As we previously showed, given that expansion increases with the number of CGG repeats and that the latter correlates with FMR1 mRNA levels, the presence of expansion could be a marker for elevated mRNA related toxicity.…”

Repeat‐Associated Non‐AUG Translation of AGAGGG Repeats that Cause X‐Linked Dystonia‐Parkinsonism

“…Although two independent genome-editing studies have established that the SVA retrotransposon insertion in TAF1 causes XDP, 19,20 the pathogenic mechanisms linking this genetic etiology to neurodegeneration in this rare disease remain unsettled. An essential clue to this longstanding issue was the observation that a polymorphic hexanucleotide repeat within this pathogenic insertion correlates with clinical disease manifestation and somatically expands in patients' brains, 8,9,14,15 implying that XDP may share causal pathways with other diseases caused by unstable repeat expansions. 16 By developing XDP-specific RAN translation reporters, our work provides the first in-vitro proof of principle that the XDP-associated hexanucleotide repeat is translated into proteins.…”

“…However, TAF1 LoF in rodents' brains failed to recapitulate the specific pattern of striatal neurodegeneration in this rare disease 12,13 . Moreover, somatic expansions of the hexanucleotide repeat mentioned above were found to occur at greater levels in the brain relative to the blood of XDP patients, hinting at the possible contribution of other repeat‐mediated pathogenic processes in XDP 14‐16 . This study investigated the potential of the XDP‐linked (AGAGGG) n repeat expansion to undergo RAN translation as a possible contributor to disease pathogenesis.…”

“…12,13 Moreover, somatic expansions of the hexanucleotide repeat mentioned above were found to occur at greater levels in the brain relative to the blood of XDP patients, hinting at the possible contribution of other repeat-mediated pathogenic processes in XDP. [14][15][16] This study investigated the potential of the XDP-linked…”

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

“…Following publication of the original article [ 1 ], the authors identified an error in the author name of Alan Mejia Maza.…”