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![HTT allele str uct ures influence HD A O O. T he upper part of the diagram represents a reference HD allele with 42 CAG repeats f ollo w ed b y the typically human 'CAA-CAG' tract, leading to a protein with 42Q + 2Q (both CAA and CAG translate to glutamine, Q). The CCG-CCA pair [representing the initial tract of the proline-rich domain (PRD)] f ollo wing the CAGs is also shown. Middle and bottom sections: GWAS-identified variants in the HTT allele nucleotide sequence that alter A O O; specifically, (middle) the LOI disease haplotype, an A-to-G synonymous mutation in the polyQ tract, leads to the same protein as the reference HD allele (42Q + 2Q), but accelerates disease onset. Con v ersely (bottom), in the DUP disease haplotype, the inclusion of an additional 'CAA-CAG' tract dela y s disease onset despite adding two extra Qs to the protein (42Q + 4Q).](publication/387062826/figure/fig2/AS:11431281303595798@1736894247717/HTT-allele-str-uct-ures-influence-HD-A-O-O-T-he-upper-part-of-the-diagram-represents-a.png)
HTT allele str uct ures influence HD A O O. T he upper part of the diagram represents a reference HD allele with 42 CAG repeats f ollo w ed b y the typically human 'CAA-CAG' tract, leading to a protein with 42Q + 2Q (both CAA and CAG translate to glutamine, Q). The CCG-CCA pair [representing the initial tract of the proline-rich domain (PRD)] f ollo wing the CAGs is also shown. Middle and bottom sections: GWAS-identified variants in the HTT allele nucleotide sequence that alter A O O; specifically, (middle) the LOI disease haplotype, an A-to-G synonymous mutation in the polyQ tract, leads to the same protein as the reference HD allele (42Q + 2Q), but accelerates disease onset. Con v ersely (bottom), in the DUP disease haplotype, the inclusion of an additional 'CAA-CAG' tract dela y s disease onset despite adding two extra Qs to the protein (42Q + 4Q).
Source publication
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. Notabl...
Contexts in source publication
Context 1
... such variant affects the penultimate triplet of the CAG repeat. In humans, the repetition of pure CAGs typically ends with a C AA-C AG segment, where the C AA, along with CAG, encodes glutamine (Q) (Figure 2 , reference). This penultimate CAA is considered an interruption in the pure CAGs stretch. ...
Context 2
... typical patient with 42 CAG repeats followed by the CAA-CAG produces a protein with 42 + 2Qs (Figure 2 , reference). ...
Context 3
... such patients with, supposedly, 42 CAG repeats would acquire an additional C AG-C AG segment in place of C AA-C AG, thereby creating a longer stretch of pure CAGs. Despite this, the number of Qs in the resulting protein remains at 42 + 2Qs ( Figure 2 , LOI). Remarkably, patients with the LOI haplotype exhibited a hastening of AOO of 25 years on average. ...
Context 4
... group of patients carried a duplication of the penultimate C AA-C AG tract (DUP, Duplication). In a hypothetical patient with 42 uninterrupted CAG repeats, this duplication will result in a protein with 42 + 4Qs, which could theoretically increase protein toxicity (Figure 2 , DUP). However, this variation is now recognized as a beneficial cis -acting modifier, leading to an average delay of 4.2 years in AOO ( 34 ). ...
Similar publications
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...
Citations
... Meera Purushottam meera.purushottam@gmail.com expansion disorders, especially in the brain, is a critical factor in disease biology [4]. Transcription-induced DNA slippage and instability may have profound biological consequences in repeat-associated neurodegenerative diseases, and account for expanded repeats in terminally differentiated cells like neurons [5]. ...
Spinocerebellar ataxia type 12 (SCA12), an autosomal dominant cerebellar ataxia, caused by an expansion of (CAG)n in the 5′ of the PPP2R2B gene on chr5q32, is common in India. The illness often manifests late in life, with diverse neurological and psychiatric symptoms, suggesting involvement of different brain regions. Prominent neuronal loss and atrophy of the cerebellum have been noted earlier. In Huntington’s disease (HD), somatic instability associated with the size of the expanded CAG allele in HTT varies across regions of the brain, and influences the nature and severity of symptoms. We estimated CAG repeat size, methylation and gene expression in the PPP2R2B gene across regions in brain tissue from a person with SCA12. We also studied the regional expression of DNA repair pathway and cell cycle genes. Somatic mosaicism, manifested as CAG repeat instability, is detected across brain regions. The cerebellum showed the least somatic instability, and this was coupled with increased methylation, and lower expression, of the PPP2R2B gene. Interestingly, increased expression of DNA maintenance pathway related genes, which might partly explain the lowered DNA instability, was also observed. There was also decreased expression of cell cycle modulators, which could initiate apoptosis, and thus account for neuronal cell death seen in the brain sections. We suggest that drugs that improve DNA repeat stability, could thus be explored as a treatment option for SCA12.
... The CAG-repeat length has an inverse relation to the age of onset. Individuals 68 with CAG repeat lengths between 8 and 26 are normal, while CAG repeat lengths of 27- 69 35 are recognized as intermediate alleles that do not lead to the disease in the carrier but 70 may increase to a pathogenic length in the progeny following germline transmission. CAG 71 repeat lengths between 36-39 may express the disease with low penetrance, whereas re-72 peat lengths exceeding 40 are fully penetrant and pathogenic [1][2][3][4]. ...
Neurodegenerative disorders (NDs) cause progressive neuronal loss and are a significant public health concern, with NDs projected to become the second leading global cause of death within two decades. Huntington’s disease (HD) is a rare, progressive ND caused by an autosomal-dominant mutation in the huntingtin (HTT) gene, leading to severe neuronal loss in the brain and resulting in debilitating motor, cognitive, and psychiatric symptoms. Given the complex pathology of HD, biomarkers are essential for performing early diagnosis, monitoring disease progression, and evaluating treatment efficacy. However, the identification of consistent HD biomarkers is challenging due to the prolonged premanifest HD stage, HD’s heterogeneous presentation, and its multiple underlying biological pathways. This study involves a 10-year bibliometric analysis of HD biomarker research, revealing key research trends and gaps. The study also features a comprehensive literature review of emerging HD biomarkers, concluding the need for better stratification of HD patients and well-designed longitudinal studies to validate HD biomarkers. Promising candidate wet HD biomarkers— including neurofilament light chain protein (NfL), microRNAs, the mutant HTT protein, and specific metabolic and inflammatory markers— are discussed, with emphasis on their potential utility in the premanifest HD stage. Additionally, biomarkers reflecting brain structural deficits and motor or behavioral impairments, such as neurophysiological (e.g., motor tapping, speech, EEG, and event-related potentials) and imaging (e.g., MRI, PET, and diffusion tensor imaging) biomarkers, are evaluated. The findings underscore that the discovery and validation of reliable HD biomarkers urgently require improved patient stratification and well-designed longitudinal studies. Reliable biomarkers, particularly in the premanifest HD stage, are crucial for optimizing HD clinical management strategies, enabling personalized treatment approaches, and advancing clinical trials of HD-modifying therapies.
... In the last few years, the field has been transformed by evidence that the pathological CAG triplets carried in genes such as HTT vary in size among different cells within affected tissues (17)(18)(19)(20). A summary of these results and their implications are provided in the accompanying review ( 157 ). This variability also suggests that the diseased brain is a mosaic of genomes ( 21 ), each carrying a genome with varying CAG sizes in the responsible gene. ...
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 (HTT) gene. Second, extreme expansions up to 800 CAG repeats have been found in specific cell types affected by the disease. Third, synonymous single nucleotide variants within the CAG repeat stretch influence the age of disease onset. Thus, new sequencing-based protocols that profile both the length and the exact nucleotide sequence of triplet repeats are crucial. Various strategies to enrich the target gene over the background, along with sequencing platforms and bioinformatic pipelines, are under development. This review discusses the concepts, challenges, and methodological opportunities for analyzing triplet repeats, using HD as a case study. Starting with traditional approaches, we will explore how sequencing-based methods have evolved to meet increasing scientific demands. We will also highlight experimental and bioinformatic challenges, aiming to provide a guide for accurate triplet repeat characterization for diagnostic and therapeutic purposes.
