A dynamic trinucleotide repeat (TNR) expansion in the DMD gene

Kekou, Kyriaki; Sofocleous, Christalena; Papadimas, George K.; Petichakis, Dimitris; Svingou, Maria; Pons, R; Vorgia, Pelagia; Gika, Artemis; Kitsiou-Tzeli, Sophia; Kanavakis, Emmanuel

doi:10.1016/j.mcp.2016.07.001

Cited by 6 publications

(4 citation statements)

References 18 publications

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“…It also predicts that in a subset of patients, an inactivation of the same gene could happen due to a missense, indel, or frameshift mutation, instead of repeat expansion. Both of these predictions are true for autosomal recessive FRDA (62), progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1) (63), Congenital insensitivity to pain (44), X-linked Duchenne muscular dystrophy (64), and fragile X syndrome (65,66).…”

Section: From Expanded Dna Repeats To Diseasementioning

confidence: 99%

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

Khristich

Mirkin

2020

Journal of Biological Chemistry

232

239

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Expansions of simple tandem repeats are responsible for almost 50 human diseases, the majority of which are severe, degenerative, and not currently treatable or preventable. In this review, we first describe the molecular mechanisms of repeat-induced toxicity, which is the connecting link between repeat expansions and pathology. We then survey alternative DNA structures that are formed by expandable repeats and review the evidence that formation of these structures is at the core of repeat instability. Next, we describe the consequences of the presence of long structure-forming repeats at the molecular level: somatic and intergenerational instability, fragility, and repeat-induced mutagenesis. We discuss the reasons for gender bias in intergenerational repeat instability and the tissue specificity of somatic repeat instability. We also review the known pathways in which DNA replication, transcription, DNA repair, and chromatin state interact and thereby promote repeat instability. We then discuss possible reasons for the persistence of disease-causing DNA repeats in the genome. We describe evidence suggesting that these repeats are a payoff for the advantages of having abundant simple-sequence repeats for eukaryotic genome function and evolvability. Finally, we discuss two unresolved fundamental questions: (i) why does repeat behavior differ between model systems and human pedigrees, and (ii) can we use current knowledge on repeat instability mechanisms to cure repeat expansion diseases?

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Section: From Expanded Dna Repeats To Diseasementioning

confidence: 99%

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

Khristich

Mirkin

2020

Journal of Biological Chemistry

232

239

View full text Add to dashboard Cite

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“…STRchive includes some tandem repeats for which there is conflicting evidence for the association of this repeat expansion with a disease. One of these is a TTC repeat expansion in DMD linked to Duchenne Muscular Dystrophy, where it was suggested that >60 repeat units is pathogenic (Kekou et al, 2016). Investigation of this repeat using pathSTR (Fig.…”

Section: Pathstr To Evaluate Pathogenic Repeatsmentioning

confidence: 99%

Medically relevant tandem repeats in nanopore sequencing of control cohorts

De Coster,

Höijer,

Bruggeman

et al. 2024

Preprint

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Research and diagnostics for medically relevant tandem repeats and repeat expansions are hampered by the lack of population-scale databases. We attempt to fill this gap using our pathSTR web tool, which leverages long-read sequencing of large cohorts to determine repeat length and sequence composition in the general population. The current version includes 878 individuals of the 1000 Genomes Project cohort sequenced on the Oxford Nanopore Technologies PromethION. A comprehensive set of medically relevant tandem repeats were genotyped using STRdust to determine the tandem repeat length and sequence composition. PathSTR provides rich visualizations of this dataset, as well as the feature to upload one's own data for comparison along the control cohort. We demonstrate the implementation of this application using data from targeted nanopore sequencing of a patient with Myotonic Dystrophy type 1. This resource will empower the genetics community to get a more complete overview of normal variation in tandem repeat length and sequence composition, and enable a better assessment of the pathogenic impact of tandem repeats observed in patients. PathSTR is available at https://pathstr.bioinf.be

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“…Expansions of short tandem repeats, particularly triplet repeat expansions, are known to be one of the major causes of neurological disorders and have also been linked to other types of disorders [ 16 , 17 ]. For example, a trinucleotide repeat expansion in DMD intron was identified in patients with myopathy [ 18 ]. Furthermore, Miyatake et al [ 19 ] succeeded in identifying pathogenic repeat expansions in several patients with neurological and neuromuscular diseases.…”

Section: Identification Of Pathogenic Structural Variants and Repeat ...mentioning

confidence: 99%

Long-read next-generation sequencing for molecular diagnosis of pediatric endocrine disorders

Kuroki,

Hattori,

Matsubara

et al. 2024

Ann Pediatr Endocrinol Metab

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Recent advances in long-read next-generation sequencing (NGS) have enabled researchers to identify several pathogenic variants overlooked by short-read NGS, array-based comparative genomic hybridization, and other conventional methods. Long-read NGS is particularly useful in the detection of structural variants and repeat expansions. Furthermore, it can be used for mutation screening in difficultto- sequence regions, as well as for DNA-methylation analyses and haplotype phasing. This mini-review introduces the usefulness of long-read NGS in the molecular diagnosis of pediatric endocrine disorders.

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A dynamic trinucleotide repeat (TNR) expansion in the DMD gene

Cited by 6 publications

References 18 publications

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

Medically relevant tandem repeats in nanopore sequencing of control cohorts

Long-read next-generation sequencing for molecular diagnosis of pediatric endocrine disorders

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