The Experts below are selected from a list of 26601 Experts worldwide ranked by ideXlab platform
Harry T Orr - One of the best experts on this subject based on the ideXlab platform.
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The Unstable Repeats - Three Evolving Faces of Neurological Disease
Neuron, 2013Co-Authors: David L. Nelson, Harry T Orr, Stephen T. WarrenAbstract:Disorders characterized by expansion of an unstable Nucleotide Repeat account for a number of inherited neurological diseases. Here, we review examples of unstable Repeat disorders that nicely illustrate three of the major pathogenic mechanisms associated with these diseases: loss of function typically by disrupting transcription of the mutated gene, RNA toxic gain of function, and protein toxic gain of function. In addition to providing insight into the mechanisms underlying these devastating neurological disorders, the study of these unstable microsatellite Repeat disorders has provided insight into very basic aspects of neuroscience.
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unstable Nucleotide Repeat minireview series a molecular biography of unstable Repeat disorders
Journal of Biological Chemistry, 2009Co-Authors: Harry T OrrAbstract:Expansion of an unstable Nucleotide Repeat is a mutational mechanism that is apparently unique to humans and is known to cause a variety of neurological disorders. This collection of minireviews examines several of these unstable Repeats, focusing on those where there is considerable molecular information on how the mutation alters function.
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Minireview prologue -- Unstable Nucleotide Repeat minireview series: A molecular biography of unstable Repeat disorders
The Journal of biological chemistry, 2008Co-Authors: Harry T OrrAbstract:Expansion of an unstable Nucleotide Repeat is a mutational mechanism that is apparently unique to humans and is known to cause a variety of neurological disorders. This collection of minireviews examines several of these unstable Repeats, focusing on those where there is considerable molecular information on how the mutation alters function.
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Increased TriNucleotide Repeat Instability with Advanced Maternal Age
Human molecular genetics, 1997Co-Authors: Michael D. Kaytor, Huda Y. Zoghbi, Eric N. Burright, Lisa A. Duvick, Harry T OrrAbstract:Nucleotide Repeat instability is associated with an increasing number of cancers and neurological disorders. The mechanisms that govern Repeat instability in these biological disorders are not well understood. To examine genetic aspects of Repeat instability we have introduced an expanded CAG triNucleotide Repeat into transgenic mice. We have detected intergenerational CAG Repeat instability in transgenic mice only when the transgene was maternally transmitted. These intergenerational instabilities increased in frequency and magnitude as the transgenic mother aged. Furthermore, triplet Repeat variations were detected in unfertilized oocytes and were comparable with those in the offspring. These data show that maternal Repeat instability in the transgenic mice occurs after meiotic DNA replication and prior to oocyte fertilization. Thus, these findings demonstrate that advanced maternal age is an important factor for instability of Nucleotide Repeats in mammalian DNA.
Peter K. Todd - One of the best experts on this subject based on the ideXlab platform.
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Enhanced detection of Nucleotide Repeat mRNA with hybridization chain reaction
2021Co-Authors: Mary Rebecca Glineburg, Sami J. Barmada, Yuan Zhang, Elizabeth M. H. Tank, Peter K. ToddAbstract:RNAs derived from expanded Nucleotide Repeats form detectable foci in patient cells and these foci are thought to contribute to disease pathogenesis. The most widely used method for detecting RNA foci is fluorescence in situ hybridization (FISH). However, FISH is prone to low sensitivity and photo-bleaching that can complicate data interpretation. Here we applied hybridization chain reaction (HCR) as an alternative approach to Repeat RNA foci detection of GC-rich Repeats in two neurodegenerative disorders: GGGGCC (G4C2) hexaNucleotide Repeat expansions in C9orf72 that cause amyotrophic lateral sclerosis and frontotemporal dementia (C9 ALS/FTD) and CGG Repeat expansions in FMR1 that cause Fragile X-associated tremor/ataxia syndrome. We found that HCR of both G4C2 and CGG Repeats has comparable specificity to traditional FISH, but is >40x more sensitive and shows Repeat-length dependence in its intensity. HCR is better than FISH at detecting both nuclear and cytoplasmic foci in human C9 ALS/FTD fibroblasts, patient iPSC derived neurons, and patient brain samples. We used HCR to determine the impact of integrated stress response (ISR) activation on RNA foci number and distribution. G4C2 Repeat RNA did not readily co-localize with the stress granule marker G3BP1, but ISR induction increased both the number of detectible nuclear RNA foci and the nuclear/cytoplasmic foci ratio in patient fibroblasts and patient derived neurons. Taken together, these data suggest that HCR can be a useful tool for detecting Repeat expansion mRNA in C9 ALS/FTD and other Repeat expansion disorders.
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The carboxyl termini of RAN translated GGGGCC Nucleotide Repeat expansions modulate toxicity in models of ALS/FTD.
Acta neuropathologica communications, 2020Co-Authors: Birttany N Flores, Amy Krans, Michelle Frazer, Sam Natla, Sarjina Niraula, Olamide Adefioye, Sami J. Barmada, Peter K. ToddAbstract:An intronic hexaNucleotide Repeat expansion in C9ORF72 causes familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This Repeat is thought to elicit toxicity through RNA mediated protein sequestration and Repeat-associated non-AUG (RAN) translation of dipeptide Repeat proteins (DPRs). We generated a series of transgenic Drosophila models expressing GGGGCC (G4C2) Repeats either inside of an artificial intron within a GFP reporter or within the 5' untranslated region (UTR) of GFP placed in different downstream reading frames. Expression of 484 intronic Repeats elicited minimal alterations in eye morphology, viability, longevity, or larval crawling but did trigger RNA foci formation, consistent with prior reports. In contrast, insertion of Repeats into the 5' UTR elicited differential toxicity that was dependent on the reading frame of GFP relative to the Repeat. Greater toxicity correlated with a short and unstructured carboxyl terminus (C-terminus) in the glycine-arginine (GR) RAN protein reading frame. This change in C-terminal sequence triggered nuclear accumulation of all three RAN DPRs. A similar differential toxicity and dependence on the GR C-terminus was observed when Repeats were expressed in rodent neurons. The presence of the native C-termini across all three reading frames was partly protective. Taken together, these findings suggest that C-terminal sequences outside of the Repeat region may alter the behavior and toxicity of dipeptide Repeat proteins derived from GGGGCC Repeats.
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the carboxyl termini of ran translated ggggcc Nucleotide Repeat expansions modulate toxicity in models of als ftd
Acta neuropathologica communications, 2020Co-Authors: Birttany N Flores, Amy Krans, Michelle Frazer, Sam Natla, Sarjina Niraula, Olamide Adefioye, Sami J. Barmada, Peter K. ToddAbstract:An intronic hexaNucleotide Repeat expansion in C9ORF72 causes familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This Repeat is thought to elicit toxicity through RNA mediated protein sequestration and Repeat-associated non-AUG (RAN) translation of dipeptide Repeat proteins (DPRs). We generated a series of transgenic Drosophila models expressing GGGGCC (G4C2) Repeats either inside of an artificial intron within a GFP reporter or within the 5' untranslated region (UTR) of GFP placed in different downstream reading frames. Expression of 484 intronic Repeats elicited minimal alterations in eye morphology, viability, longevity, or larval crawling but did trigger RNA foci formation, consistent with prior reports. In contrast, insertion of Repeats into the 5' UTR elicited differential toxicity that was dependent on the reading frame of GFP relative to the Repeat. Greater toxicity correlated with a short and unstructured carboxyl terminus (C-terminus) in the glycine-arginine (GR) RAN protein reading frame. This change in C-terminal sequence triggered nuclear accumulation of all three RAN DPRs. A similar differential toxicity and dependence on the GR C-terminus was observed when Repeats were expressed in rodent neurons. The presence of the native C-termini across all three reading frames was partly protective. Taken together, these findings suggest that C-terminal sequences outside of the Repeat region may alter the behavior and toxicity of dipeptide Repeat proteins derived from GGGGCC Repeats.
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The carboxyl-terminus of RAN translated GGGGCC Nucleotide Repeat expansions modulates toxicity in models of ALS/FTD
2020Co-Authors: Birttany N Flores, Amy Krans, Michelle Frazer, Sam Natla, Sarjina Niraula, Olamide Adefioye, Sami J. Barmada, Peter K. ToddAbstract:An intronic hexaNucleotide Repeat expansion in C9ORF72 causes familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This Repeat is thought to elicit toxicity through RNA mediated protein sequestration and Repeat-associated non-AUG (RAN) translation of dipeptide Repeat proteins (DPRs). We generated a series of transgenic Drosophila models expressing GGGGCC (G4C2) Repeats either inside of an artificial intron within a GFP reporter or within the 5-prime UTR of GFP placed in different downstream reading frames. Expression of 484 intronic Repeats elicited minimal alterations in eye morphology, viability, longevity, or larval crawling but did trigger RNA foci formation, consistent with prior reports. In contrast, insertion of Repeats into the 5-prime UTR elicited differential toxicity that was dependent on the reading frame of GFP relative to the Repeat. Greater toxicity correlated with a short and unstructured carboxyl terminus in the glycine-arginine (GR) RAN protein reading frame. This change in C-terminal sequence triggered nuclear accumulation of all three RAN DPRs. A similar differential toxicity and dependence on the GR carboxyl terminus was observed when Repeats were expressed in rodent neurons. The presence of the native carboxyl-termini across all three reading frames was partly protective. Taken together, these findings suggest that carboxyl terminal sequences outside of the Repeat region may alter the behavior and toxicity of dipeptide Repeat proteins derived from GGGGCC Repeats.
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the carboxyl terminus of ran translated ggggcc Nucleotide Repeat expansions modulates toxicity in models of als ftd
bioRxiv, 2020Co-Authors: Birttany N Flores, Amy Krans, Michelle Frazer, Sam Natla, Sarjina Niraula, Olamide Adefioye, Sami J. Barmada, Peter K. ToddAbstract:An intronic hexaNucleotide Repeat expansion in C9ORF72 causes familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This Repeat is thought to elicit toxicity through RNA mediated protein sequestration and Repeat-associated non-AUG (RAN) translation of dipeptide Repeat proteins (DPRs). We generated a series of transgenic Drosophila models expressing GGGGCC (G4C2) Repeats either inside of an artificial intron within a GFP reporter or within the 5-prime UTR of GFP placed in different downstream reading frames. Expression of 484 intronic Repeats elicited minimal alterations in eye morphology, viability, longevity, or larval crawling but did trigger RNA foci formation, consistent with prior reports. In contrast, insertion of Repeats into the 5-prime UTR elicited differential toxicity that was dependent on the reading frame of GFP relative to the Repeat. Greater toxicity correlated with a short and unstructured carboxyl terminus in the glycine-arginine (GR) RAN protein reading frame. This change in C-terminal sequence triggered nuclear accumulation of all three RAN DPRs. A similar differential toxicity and dependence on the GR carboxyl terminus was observed when Repeats were expressed in rodent neurons. The presence of the native carboxyl-termini across all three reading frames was partly protective. Taken together, these findings suggest that carboxyl terminal sequences outside of the Repeat region may alter the behavior and toxicity of dipeptide Repeat proteins derived from GGGGCC Repeats.
M Frommer - One of the best experts on this subject based on the ideXlab platform.
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the bactrocera tryoni homologue of the drosophila melanogaster sex determination gene doublesex
Insect Molecular Biology, 1998Co-Authors: D. C. A. Shearman, M FrommerAbstract:A homologue of the bifunctional sex-determining gene, doublesex (dsx), has been identified in the tephritid fruit fly, Bactrocera tryoni, and has been found to be expressed in a sex-specific manner in adult flies. The male- and female-specific cDNAs are identical at their 5' ends but differ at their 3' ends and appear to be the products of alternate splicing. The level of identity of the sex-specific DSX proteins of B. tryoni with the D. melanogaster DSX proteins, across the region corresponding to the DNA binding domain and the oligomerization domains, is greater than 85%. Four sequence motifs which are ten to thirteen bases identical to the TRA/TRA-2 binding sites (thirteen-Nucleotide Repeat sequences) are present in the female-specific exon of the B. tryoni dsx gene.
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The Bactrocera tryoni homologue of the Drosophila melanogaster sex‐determination gene doublesex
Insect molecular biology, 1998Co-Authors: D. C. A. Shearman, M FrommerAbstract:A homologue of the bifunctional sex-determining gene, doublesex (dsx), has been identified in the tephritid fruit fly, Bactrocera tryoni, and has been found to be expressed in a sex-specific manner in adult flies. The male- and female-specific cDNAs are identical at their 5' ends but differ at their 3' ends and appear to be the products of alternate splicing. The level of identity of the sex-specific DSX proteins of B. tryoni with the D. melanogaster DSX proteins, across the region corresponding to the DNA binding domain and the oligomerization domains, is greater than 85%. Four sequence motifs which are ten to thirteen bases identical to the TRA/TRA-2 binding sites (thirteen-Nucleotide Repeat sequences) are present in the female-specific exon of the B. tryoni dsx gene.
Stephen T. Warren - One of the best experts on this subject based on the ideXlab platform.
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The Unstable Repeats - Three Evolving Faces of Neurological Disease
Neuron, 2013Co-Authors: David L. Nelson, Harry T Orr, Stephen T. WarrenAbstract:Disorders characterized by expansion of an unstable Nucleotide Repeat account for a number of inherited neurological diseases. Here, we review examples of unstable Repeat disorders that nicely illustrate three of the major pathogenic mechanisms associated with these diseases: loss of function typically by disrupting transcription of the mutated gene, RNA toxic gain of function, and protein toxic gain of function. In addition to providing insight into the mechanisms underlying these devastating neurological disorders, the study of these unstable microsatellite Repeat disorders has provided insight into very basic aspects of neuroscience.
Doug E Bader - One of the best experts on this subject based on the ideXlab platform.
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Single-Nucleotide Repeat Analysis for Subtyping Bacillus anthracis Isolates
Journal of clinical microbiology, 2006Co-Authors: Chad W. Stratilo, Christopher T. Lewis, Louis Bryden, Michael R. Mulvey, Doug E BaderAbstract:Single-Nucleotide Repeats (SNRs) are variable-number tandem Repeats that display very high mutation rates. In an outbreak situation, the use of a marker system that exploits regions with very high mutation rates, such as SNRs, allows the differentiation of isolates with extremely low levels of genetic diversity. This report describes the identification and analysis of SNR loci of Bacillus anthracis. SNR loci were selected in silico, and the loci with the highest diversity were used to design and test locus-specific primers against a number of B. anthracis strains with the same multilocus variable-number tandem Repeat analysis (MLVA) genotype. SNR markers that allowed strains with the same MLVA genotype to be differentiated from each other were identified. The resulting SNR marker system can be used as a molecular epidemiological tool in a natural outbreak or bioterrorism event, offering the best chance of distinguishing very closely related isolates.
