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The accurate characterization of triplet repeats, especially the overrepresented CAG repeats, is increasingly relevant for several reasons. First, germline expansion of CAG repeats above a gene-specific threshold causes multiple neurodegenerative disorders; for instance, Huntington’s disease (HD) is triggered by >36 CAG repeats in the huntingtin (H...
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... ( 17 ), or for ruling out expanded alleles when sequencing two alleles with below-threshold repeat counts ( 66 ), it may fall short for fully characterizing expanded alleles in disorders like DM2 ( 39 ). Table 2 highlights HD studies that utilized MiSeq for HTT CAG sizing, discussing its utility and limitations. Recent investigations by Ciosi et al. ( 38 ) and Mätlik et al. ( 17 ) used MiSeq to size expanded HTT CAG repeats, achieving resolutions up to ∼110 CAG repeats with as little as 20 ng of genomic DNA. ...Context 2
... was evidenced by comparisons with Small pool-PCR and bulk-PCR capillary electrophoresis on the same samples. The comparisons revealed that longer triplet repeats were largely missed by PacBio HiFi sequencing of bulk PCR products, despite some PacBio CCS reads with over 450 CAG repeats ( 38 ) ( Table 2 ). ...Context 3
... Tsai et al . ( 107 ) and Höijer et al. ( 113 ) have used the PacBio no-Amp protocol, starting with blood samples from HD patients, detecting up to 60 CAG repeats (Table 2 ). These protocols have not yet been thoroughly tested on HD brain samples; however, they may represent the most unbiased strategy for detecting rare extreme expansions in affected tissues. ...Context 4
... initial read portion is computationally compared to a target sequence, and a quick decision is made to either fully sequence the molecule (if it matches the target) or reverse the voltage across the pore to eject the read, replacing it with a new one ( 121 ). Adaptive (Table 2 ). This system represents a significant advantage for CAG sizing in HD and other triplet repeat diseases because it does not require any laborious ad hoc enrichment protocols. ...Context 5
... minimize alignment issues, which may be frequent in case of long repeat expansions, Taylor and colleagues ( 128 ) developed RD, an alignment-free tool flexible enough to work with datasets from multiple repeated motifs and sequencing platforms, such as Illumina MiSeq and PacBio HiFi. Notably, RD showed high agreement with available tools on 609 PCR-amplified blood-derived samples from HD, predicting the same modal allele length for 98.3% of the samples compared to ScaleHD ( 128 ) ( Table 2 ). ...Citations
... In these studies, the precise measurement of CAG size and composition in individual brain cells, along with the corresponding transcriptional profiles, has become increasingly important. These aspects are discussed in detail in the accompanying article by some of the authors ( 17 ). Finally, we will review strategies aimed at reducing SI with the goal of fighting the disease. ...
... More recently, two pioneering studies analyzing postmortem human HD brains demonstrated that SI rates are not only organ and tissue-specific [SI is marked in the brain striatum, but only moderate in the cerebellum ( 21 )], but also cell-type specific, with MSNs-the most vulnerable cells in HD-showing the highest levels of instability ( 22 ,28 ) (Figure 1 ). These advancements have been made possible by continuous improvements in genomic and CAG sequencing technologies, as detailed in the accompanying paper by some of the authors ( 17 ). For example, Mätlik and colleagues developed a fluorescence-activated nuclear sorting (FANS) approach to isolate different cell populations from five post-mortem HD brains based on marker gene expression. ...
... Since HD phenotypes, such as SI, transcriptional dysregulation and mHTT aggregation formation ( 28 ,51 ) are often co-modulated, SI in HD-vulnerable cell types may serve as an effective early marker for potential therapies. However, to ensure consistency across studies, rigorous standards for target enrichment, sequencing methods and bioinformatics protocols will be essential ( 17 ), potentially guiding the development of clinical guidelines for SI monitoring and HD prognosis assessment. ...
Trinucleotide repeats in DNA exhibit a dual nature due to their inherent instability. While their rapid expansion can diversify gene expression during evolution, exceeding a certain threshold can lead to diseases such as Huntington’s disease (HD), a neurodegenerative condition, triggered by >36 C–A–G repeats in exon 1 of the Huntingtin gene. Notably, the discovery of somatic instability (SI) of the tract allows these mutations, inherited from an affected parent, to further expand throughout the patient’s lifetime, resulting in a mosaic brain with specific neurons exhibiting variable and often extreme CAG lengths, ultimately leading to their death. Genome-wide association studies have identified genetic variants—both cis and trans, including mismatch repair modifiers—that modulate SI, as shown in blood cells, and influence HD’s age of onset. This review will explore the evidence for SI in HD and its role in disease pathogenesis, as well as the therapeutic implications of these findings. We conclude by emphasizing the urgent need for reliable methods to quantify SI for diagnostic and prognostic purposes.
p53 plays a critical role in the pathogenesis of central nervous system (CNS) diseases, including neurodegenerative diseases, stroke, and neurodevelopmental disorders. Recent studies have shown that p53 regulates pathological processes such as apoptosis, ferroptosis, neuroinflammation, mitochondrial dysfunction, DNA damage, and synaptic dysfunction through complex molecular pathways. Preclinical studies have demonstrated that pharmacological inhibition or knockdown of p53 exerts neuroprotective effects, suggesting its potential therapeutic value. This review systematically summarizes the mechanisms of p53 in CNS diseases and the associated signaling pathways involved in these pathological processes. Additionally, p53‐related intervention strategies in CNS diseases and challenges to the development of p53‐targeted drugs are summarized, aiming to provide new insights for therapeutic treatment.
