Pathogenic CANVAS-causing but not nonpathogenic RFC1 DNA/RNA repeat motifs form quadruplex or triplex structures

Abdi, Mohammad Hossein; Zamiri, Bita; Pazuki, Gholamreza; Sardari, Soroush; Pearson, Christopher E.

doi:10.1016/j.jbc.2023.105202

Cited by 11 publications

(9 citation statements)

References 73 publications

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“…Noteworthy, the non-pathogenic AAGGAG RNA sequences can form a parallel G4 while pathogenic AAG repeats form an A-form RNA. G4 structures formed by other repeat expansions, including those found in RFC1/CANVAS, have been previously linked to a decrease in gene expression 44 . Furthermore, intronic AAG repeat expansions leading to Friedreich ataxia were shown to form R-loops that impair the transcription of FXN [45][46][47] .…”

Section: Discussionmentioning

confidence: 97%

Unveiling pathogenic and non-pathogenic FGF14 repeat expansions: identification, sequence, and secondary structure

Depienne,

Mohren,

Erdlenbruch

et al. 2024

Preprint

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Repeat expansions in FGF14cause autosomal dominant late-onset cerebellar ataxia (SCA27B), with pathogenic thresholds estimated between 250 and 300 AAG repeats. However, the complete sequences of pathogenic and non-pathogenic alleles remain largely unknown. Here, we identify FGF14 repeat expansions as the most commonly missed cause of cerebellar ataxia using a combination of short-read genome sequencing, long-range PCR and nanopore sequencing. We compare FGF14 alleles in 154 patients with ataxia and 802 controls and report an enrichment of pure FGF14 expansions above 180-220 repeats in patients. Conversely, AAGGAG and interrupted alleles are more frequent in controls. Distinct 5'-flanking regions correlate with repeat stability. SCA27B patients have a characteristic phenotype, including frequent episodic ataxia and downbeat nystagmus, similar to those with a novel nonsense variant (SCA27A). Interestingly, pathogenic and non-pathogenic repeats form different secondary structures. Our results emphasize the importance of sequencing both the repeat expansion and its flanking region for accurate clinical interpretation.

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Section: Discussionmentioning

confidence: 97%

Unveiling pathogenic and non-pathogenic FGF14 repeat expansions: identification, sequence, and secondary structure

Depienne,

Mohren,

Erdlenbruch

et al. 2024

Preprint

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“… 34 Moreover, it was shown that a G-quadruplex ligand (TMPyP4) binds specifically to the pathogenic repeats' quadruplexes. 35 These findings are promising toward understanding the disease pathogenicity and development of targeted therapies.…”

Section: Discussionmentioning

confidence: 99%

“…Thus far, structure functional analyses have been performed in vitro to study the formation of possible unusual DNA structures by short pathogenic AAGGG repeats compared with the non-pathogenic AAAAG repeats. 34 , 35 Of interest, it was shown that the pathogenic repeats can form triplex and quadruplex structures, thus leading to replication stalling in an orientation-dependent manner. 34 Moreover, it was shown that a G-quadruplex ligand (TMPyP4) binds specifically to the pathogenic repeats' quadruplexes.…”

Section: Discussionmentioning

confidence: 99%

RFC1 Repeat Distribution in the Cypriot Population

Votsi,

Tomazou,

Nicolaou

et al. 2024

Neurol Genet

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Background and Objectives The intronic biallelic AAGGG expansion in the replication factor C subunit 1 ( RFC1 ) gene was recently associated with a phenotype combining cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, as well as with late-onset ataxia. Following this discovery, studies in multiple populations extended the phenotypic and genotypic spectrum of this locus. Multiple benign and additional pathogenic configurations are currently known. Our main objectives were to study the prevalence of the pathogenic AAGGG expansion in the Cypriot population, to further characterize the RFC1 repeat locus allele distribution, and to search for possible novel repeat configurations. Methods Cypriot undiagnosed patients, in the majority presenting at least with cerebellar ataxia and non-neurologic disease controls, were included in this study. A combination of conventional methods was used, including standard PCR flanking the repeat region, repeat-primed PCR, long-range PCR, and Sanger sequencing. Bioinformatics analysis of already available in-house short-read whole-genome sequencing data was also performed. Results A large group of undiagnosed patients (n = 194), mainly presenting with pure ataxia or with ataxia accompanied by neuropathy or additional symptoms, as well as a group of non-disease controls (n = 100), were investigated in the current study. Our findings include the diagnosis of 10 patients homozygous for the pathogenic AAGGG expansion and a high percentage of heterozygous AAGGG carriers in both groups. The benign AAAAG n , AAAGG n , and AAGAG n configurations were also identified in our cohorts. We also report and discuss the identification of 2 recently reported novel and possibly benign repeat configurations, AAAGGG n and AAGAC n , thus confirming their existence in another distinct population, and we highlight an increased frequency of the AAAGGG n in the patient group, including a single case of homozygosity. Discussion Our findings indicate the existence of genetic heterogeneity regarding the RFC1 repeat configurations and that the AAGGG pathogenic expansion is a frequent cause of ataxia in the Cypriot population.

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“…Recently, Abdi et al. have reported that AAGGG repeats formed G4 structures in vitro primarily based on circular dichroism (CD) spectroscopic analysis ( 32 ). However, the high-resolution structures of AAGGG repeats, which can shed light on ligand design and pathogenic mechanism study, remain unavailable.…”

Section: Introductionmentioning

confidence: 99%

Structural investigation of pathogenic RFC1 AAGGG pentanucleotide repeats reveals a role of G-quadruplex in dysregulated gene expression in CANVAS

Wang,

Yan

et al. 2024

Nucleic Acids Research

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An expansion of AAGGG pentanucleotide repeats in the replication factor C subunit 1 (RFC1) gene is the genetic cause of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), and it also links to several other neurodegenerative diseases including the Parkinson's disease. However, the pathogenic mechanism of RFC1 AAGGG repeat expansion remains enigmatic. Here, we report that the pathogenic RFC1 AAGGG repeats form DNA and RNA parallel G-quadruplex (G4) structures that play a role in impairing biological processes. We determine the first high-resolution nuclear magnetic resonance (NMR) structure of a bimolecular parallel G4 formed by d(AAGGG)2AA and reveal how AAGGG repeats fold into a higher-order structure composed of three G-tetrad layers, and further demonstrate the formation of intramolecular G4s in longer DNA and RNA repeats. The pathogenic AAGGG repeats, but not the nonpathogenic AAAAG repeats, form G4 structures to stall DNA replication and reduce gene expression via impairing the translation process in a repeat-length-dependent manner. Our results provide an unprecedented structural basis for understanding the pathogenic mechanism of AAGGG repeat expansion associated with CANVAS. In addition, the high-resolution structures resolved in this study will facilitate rational design of small-molecule ligands and helicases targeting G4s formed by AAGGG repeats for therapeutic interventions.

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Pathogenic CANVAS-causing but not nonpathogenic RFC1 DNA/RNA repeat motifs form quadruplex or triplex structures

Cited by 11 publications

References 73 publications

Unveiling pathogenic and non-pathogenic FGF14 repeat expansions: identification, sequence, and secondary structure

Unveiling pathogenic and non-pathogenic FGF14 repeat expansions: identification, sequence, and secondary structure

RFC1 Repeat Distribution in the Cypriot Population

Structural investigation of pathogenic RFC1 AAGGG pentanucleotide repeats reveals a role of G-quadruplex in dysregulated gene expression in CANVAS

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