Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0016719 (Friedreich's ataxia)
 2,098 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Friedreich ataxia (FRDA) is a member of the Repeat Expansion Diseases, a group of genetic conditions resulting from an increase/expansion in the size of a specific tandem array. FRDA results from expansion of a GAA/TTC-tract in the first intron of the frataxin gene (FXN). The disease-associated tandem repeats all form secondary structures that are thought to contribute to the propensity of the repeat to expand. The subset of these diseases that result from a CGG/CCG-repeat expansion, such as Fragile X syndrome, also express a folate-sensitive fragile site coincident with the repeat on the affected chromosome. This chromosome fragility involves the generation of chromosome/chromatid gaps or breaks, or the high frequency loss of one or both copies of the affected gene when cells are grown under folate stress or as we showed previously, in the presence of an inhibitor of the ATM checkpoint kinase. Whether Repeat Expansion Disease loci containing different repeats form similar fragile sites was not known. We show here that the region of chromosome 9 that contains the FXN locus is intrinsically prone to breakage in vivo even in control cells. However, like FXS alleles, FRDA alleles show significantly elevated levels of chromosome abnormalities in the presence of an ATM inhibitor, consistent with the formation of a fragile site.
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PMID:Evidence for chromosome fragility at the frataxin locus in Friedreich ataxia. 2637 1

Genome engineering technology using engineered nucleases has been rapidly developing, enabling the efficient correction of simple mutations. However, the precise correction of structural variations (SVs) such as large inversions remains limited. Here we describe a detailed procedure for the modeling or correction of large chromosomal rearrangements and short nucleotide repeat expansions using engineered nucleases in human induced pluripotent stem cells (hiPSCs) from a healthy donor and patients with SVs. This protocol includes the delivery of engineered nucleases with no donor template to hiPSCs, and genotyping and derivation/characterization of gene-manipulated hiPSC clones. With engineered nucleases, genomic inversions, reversions, and deletions of short nucleotide expansions can be identified in 2 weeks, and desired clones can be generated in as little as 3-4 weeks. This protocol enables the correction of large inverted segments and short nucleotide repeat expansions in diseases such as hemophilia A, fragile X syndrome, Hunter syndrome, and Friedreich's ataxia.
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PMID:Modeling and correction of structural variations in patient-derived iPSCs using CRISPR/Cas9. 2771 Oct 53

R-loops comprise an RNA/DNA hybrid and a displaced single-stranded DNA. They play crucial biological functions and are implicated in neurological diseases, including ataxias, amyotrophic lateral sclerosis, nucleotide expansion disorders (Friedreich ataxia and fragile X syndrome), and cancer. Currently, it is unclear which mechanisms cause R-loop structures to become pathogenic. The RNA/DNA helicase senataxin (SETX) is one of the best characterised R-loop-binding factors in vivo. Mutations in SETX are linked to two neurodegenerative disorders: ataxia with oculomotor apraxia type 2 (AOA2) and amyotrophic lateral sclerosis type 4 (ALS4). SETX is known to play a role in transcription, neurogenesis, and antiviral response. Here, we review the causes of R-loop dysregulation in neurodegenerative diseases and how these structures contribute to pathomechanisms. We will discuss the importance of SETX as a genome guardian in suppressing aberrant R-loop formation and analyse how SETX mutations can lead to neurodegeneration in AOA2/ALS4. Finally, we will discuss the implications for other R-loop-associated neurodegenerative diseases and point to future therapeutic approaches to treat these disorders.
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PMID:Senataxin: Genome Guardian at the Interface of Transcription and Neurodegeneration. 2777 83

Identifying large expansions of short tandem repeats (STRs), such as those that cause amyotrophic lateral sclerosis (ALS) and fragile X syndrome, is challenging for short-read whole-genome sequencing (WGS) data. A solution to this problem is an important step toward integrating WGS into precision medicine. We developed a software tool called ExpansionHunter that, using PCR-free WGS short-read data, can genotype repeats at the locus of interest, even if the expanded repeat is larger than the read length. We applied our algorithm to WGS data from 3001 ALS patients who have been tested for the presence of the C9orf72 repeat expansion with repeat-primed PCR (RP-PCR). Compared against this truth data, ExpansionHunter correctly classified all (212/212, 95% CI [0.98, 1.00]) of the expanded samples as either expansions (208) or potential expansions (4). Additionally, 99.9% (2786/2789, 95% CI [0.997, 1.00]) of the wild-type samples were correctly classified as wild type by this method with the remaining three samples identified as possible expansions. We further applied our algorithm to a set of 152 samples in which every sample had one of eight different pathogenic repeat expansions, including those associated with fragile X syndrome, Friedreich's ataxia, and Huntington's disease, and correctly flagged all but one of the known repeat expansions. Thus, ExpansionHunter can be used to accurately detect known pathogenic repeat expansions and provides researchers with a tool that can be used to identify new pathogenic repeat expansions.
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PMID:Detection of long repeat expansions from PCR-free whole-genome sequence data. 2888 2

Improper DNA double-strand break (DSB) repair results in complex genomic rearrangements (CGRs) in many cancers and various congenital disorders in humans. Trinucleotide repeat sequences, such as (GAA)n repeats in Friedreich's ataxia, (CTG)n repeats in myotonic dystrophy, and (CGG)n repeats in fragile X syndrome, are also subject to double-strand breaks within the repetitive tract followed by DNA repair. Mapping the outcomes of CGRs is important for understanding their causes and potential phenotypic effects. However, high-resolution mapping of CGRs has traditionally been a laborious and highly skilled process. Recent advances in long-read DNA sequencing technologies, specifically Nanopore sequencing, have made possible the rapid identification of CGRs with single base pair resolution. Here, we have used whole-genome Nanopore sequencing to characterize several CGRs that originated from naturally occurring DSBs at (GAA)n microsatellites in Saccharomyces cerevisiae These data gave us important insights into the mechanisms of DSB repair leading to CGRs.
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PMID:Nanopore sequencing of complex genomic rearrangements in yeast reveals mechanisms of repeat-mediated double-strand break repair. 2911 82

More than 40 diseases, most of which primarily affect the nervous system, are caused by expansions of simple sequence repeats dispersed throughout the human genome. Expanded trinucleotide repeat diseases were discovered first and remain the most frequent. More recently tetra-, penta-, hexa-, and even dodeca-nucleotide repeat expansions have been identified as the cause of human disease, including some of the most common genetic disorders seen by neurologists. Repeat expansion diseases include both causes of myotonic dystrophy (DM1 and DM2), the most common genetic cause of amyotrophic lateral sclerosis/frontotemporal dementia (C9ORF72), Huntington disease, and eight other polyglutamine disorders, including the most common forms of dominantly inherited ataxia, the most common recessive ataxia (Friedreich ataxia), and the most common heritable mental retardation (fragile X syndrome). Here I review distinctive features of this group of diseases that stem from the unusual, dynamic nature of the underlying mutations. These features include marked clinical heterogeneity and the phenomenon of clinical anticipation. I then discuss the diverse molecular mechanisms driving disease pathogenesis, which vary depending on the repeat sequence, size, and location within the disease gene, and whether the repeat is translated into protein. I conclude with a brief clinical and genetic description of individual repeat expansion diseases that are most relevant to neurologists.
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PMID:Repeat expansion diseases. 2932 6

Epigenetics is a growing field of knowledge that is changing our understanding of pathologic processes. For many cerebellar disorders, recent discoveries of epigenetic mechanisms help us to understand their pathophysiology. In this chapter, a short explanation of each epigenetic mechanism (including methylation, histone modification, and miRNA) is followed by references to those cerebellar disorders in which relevant epigenetic advances have been made. The importance of normal timing and distribution of methylation during neurodevelopment is explained. Abnormal methylation and altered gene expression in the developing cerebellum have been related to neurodevelopmental disorders such as autism, Rett syndrome, and fragile X syndrome. DNA packaging by histones is another important epigenetic mechanism in cerebellar functioning. Current knowledge of histone abnormalities in cerebellar diseases such as Friedreich ataxia and spinocerebellar ataxias is reviewed, including implications for new therapeutic approaches to these degenerative diseases. Finally, micro RNAs, the third mechanism to modulate DNA expression, and their role in normal cerebellar development and disease are described. Understanding how genetic and epigenetic mechanisms interact not only in normal cerebellar development but also in disease is a great challenge. However, such understanding will lead to promising new therapeutic possibilities as is already occurring in other areas of medicine.
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PMID:Epigenetic cerebellar diseases. 2989 Oct 61

Expansions of simple trinucleotide repeats, such as (CGG)n, (CAG)n or (GAA)n, are responsible for more than 40 hereditary disorders in humans including fragile X syndrome, Huntington's disease, myotonic dystrophy, and Friedreich's ataxia. While the mechanisms of repeat expansions were intensively studied for over two decades, the final picture has yet to emerge. It was important, therefore, to develop a mammalian experimental system for studying repeat instability, which would recapitulate repeat instability observed in human pedigrees. Here, we describe a genetically tractable experimental system to study the instability of (CGG)n repeats in cultured mammalian cells (Kononenko et al., Nat Struct Mol Biol 25:669-676, 2018). It is based on a selectable cassette carrying the HyTK gene under the control of the FMR1 promoter with carrier-size (CGG)n repeats in its 5' UTR, which was integrated into the unique RL5 site in murine erythroid leukemia cells. Expansions of these repeats and/or repeat-induced mutagenesis shut down the reporter, which results in the accumulation of ganciclovir-resistance cells. This system is useful for understanding the genetic controls of repeat instability in mammalian cells. In the long run, it can be adjusted to screen for drugs that either alleviate repeat expansions or reactivate the FMR1 promoter.
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PMID:Experimental System to Study Instability of (CGG)n Repeats in Cultured Mammalian Cells. 3158 46


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