scholarly journals The quest towards understanding the molecular pathogenesis of triplet repeat disorders: Huntingtons Disease and Fragile X-Associated Tremor and Ataxia Syndrome

2020 ◽  
Author(s):  
Alana Amado ◽  
Alana Amado
Keyword(s):  
Protein Interactions ◽  
Trinucleotide Repeat ◽  
Fragile X ◽  
Neurological Diseases ◽  
Neuronal Loss ◽  
Threshold Effect ◽  
Cag Repeats ◽  
Huntingtin Protein ◽  
Cgg Repeats ◽  
Neuronal Processes

Trinucleotide repeat disorders encompass a group of neurological diseases driven by unstable repeat expansions. Huntingtons disease (HD) is characterized by chorea and brain atrophy. The normal huntingtin protein contains 6-34 CAG repeats; however, upon a threshold effect of >36 repeats, the huntingtin protein acquires toxic mechanisms that are harmful to the cell. Fragile X-Associated Tremor and Ataxia (FXTAS) is characterized by tremor, ataxia and neuronal loss. The normal FMR1 gene contains 5-45 CGG repeats; however, upon a premutation CGG expansion of 55-200, FXTAS arises. A pathological hallmark of these disorders includes aggregate formation within the brain; suggestive of impaired protein and mRNA function. Furthermore, important molecules have been found to be sequestered into these aggregates withdrawing them from their normal roles. In this review, the ways mutant huntingtin and FMR1mRNA aggregates induce intracellular dysfunction in HD and FXTAS is analyzed, specifically in the context of impaired neuronal processes and protein-protein interactions. Analysis revealed that huntingtin and FMR1 mRNA are involved in the regulation of multiple cellular pathways; and whose impaired function results in a detrimental domino-effect that is destructive to the cell. The understanding of these molecular processes hopes to identify potential targets towards the treatment of HD and FXTAS

scholarly journals The quest towards understanding the molecular pathogenesis of triplet repeat disorders: Huntingtons Disease and Fragile X-Associated Tremor and Ataxia Syndrome

2020 ◽  
Author(s):  
Alana Alvarez-Amado
Keyword(s):  
Protein Interactions ◽  
Trinucleotide Repeat ◽  
Fragile X ◽  
Neurological Diseases ◽  
Neuronal Loss ◽  
Threshold Effect ◽  
Cag Repeats ◽  
Huntingtin Protein ◽  
Neuronal Processes ◽  
Fmr1 Mrna

Trinucleotide repeat disorders encompass a group of neurological diseases driven by unstable repeat expansions. Huntingtons disease (HD) is characterized by chorea and brain atrophy. The normal huntingtin protein contains 6-34 CAG repeats; however, upon a threshold effect of >36 repeats, the huntingtin protein acquires toxic mechanisms that are harmful to the cell. Fragile X-Associated Tremor and Ataxia (FXTAS) is characterized by tremor, ataxia and neuronal loss. The normal FMR1 gene contains 5-45 CGG repeats; however, upon a premutation CGG expansion of 55-200, FXTAS arises. A pathological hallmark of these disorders includes aggregate formation within the brain; suggestive of impaired protein and mRNA function. Furthermore, important molecules have been found to be sequestered into these aggregates withdrawing them from their normal roles. In this review, the ways mutant huntingtin and FMR1 mRNA aggregates induce intracellular dysfunction in HD and FXTAS is analyzed, specifically in the context of impaired neuronal processes and protein-protein interactions. Analysis revealed that huntingtin and FMR1 mRNA are involved in the regulation of multiple cellular pathways; and whose impaired function results in a detrimental domino-effect that is destructive to the cell. The understanding of these molecular processes hopes to identify potential targets towards the treatment of HD and FXTAS.

scholarly journals Beyond Trinucleotide Repeat Expansion in Fragile X Syndrome: Rare Coding and Noncoding Variants in FMR1 and Associated Phenotypes

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1669
Author(s):  
Cedrik Tekendo-Ngongang ◽  
Angela Grochowsky ◽  
Benjamin D. Solomon ◽  
Sho T. Yano
Keyword(s):  
Copy Number ◽  
Trinucleotide Repeat ◽  
De Novo ◽  
Fragile X ◽  
Copy Number Variants ◽  
Repeat Expansion ◽  
Full Mutation ◽  
Cgg Repeat ◽  
Testing Strategies ◽  
Cgg Repeats

FMR1 (FMRP translational regulator 1) variants other than repeat expansion are known to cause disease phenotypes but can be overlooked if they are not accounted for in genetic testing strategies. We collected and reanalyzed the evidence for pathogenicity of FMR1 coding, noncoding, and copy number variants published to date. There is a spectrum of disease-causing FMR1 variation, with clinical and functional evidence supporting pathogenicity of five splicing, five missense, one in-frame deletion, one nonsense, and four frameshift variants. In addition, FMR1 deletions occur in both mosaic full mutation patients and as constitutional pathogenic alleles. De novo deletions arise not only from full mutation alleles but also alleles with normal-sized CGG repeats in several patients, suggesting that the CGG repeat region may be prone to genomic instability even in the absence of repeat expansion. We conclude that clinical tests for potentially FMR1-related indications such as intellectual disability should include methods capable of detecting small coding, noncoding, and copy number variants.

scholarly journals Group Testing Approach for Trinucleotide Repeat Expansion Disorder Screening

2016 ◽  
Vol 62 (10) ◽  
pp. 1401-1408 ◽  
Author(s):  
Kristjan Eerik Kaseniit ◽  
Mark R Theilmann ◽  
Alexander Robertson ◽  
Eric A Evans ◽  
Imran S Haque
Keyword(s):  
Trinucleotide Repeat ◽  
Fragile X ◽  
Group Testing ◽  
Low Complexity ◽  
Repeat Expansion ◽  
Trinucleotide Repeat Expansion ◽  
Cgg Repeats ◽  
Fold Reduction ◽  
Repeat Expansions ◽  
Nonadaptive Group Testing

Abstract BACKGROUND Fragile X syndrome (FXS, OMIM #300624) is an X-linked condition caused by trinucleotide repeat expansions in the 5′ UTR (untranslated region) of the fragile X mental retardation 1 (FMR1) gene. FXS testing is commonly performed in expanded carrier screening and has been proposed for inclusion in newborn screening. However, because pathogenic alleles are long and have low complexity (>200 CGG repeats), FXS is currently tested by a single-plex electrophoresis-resolved PCR assay rather than multiplexed approaches like next-generation sequencing or mass spectrometry. In this work, we sought an experimental design based on nonadaptive group testing that could accurately and reliably identify the size of abnormally expanded FMR1 alleles of males and females. METHODS We developed a new group testing scheme named StairCase (SC) that was designed to the constraints of the FXS testing problem, and compared its performance to existing group testing schemes by simulation. We experimentally evaluated SC's performance on 210 samples from the Coriell Institute biorepositories using pooled PCR followed by capillary electrophoresis on 3 replicates of each of 3 pooling layouts differing by the mapping of samples to pools. RESULTS The SC pooled PCR approach demonstrated perfect classification of samples by clinical category (normal, intermediate, premutation, or full mutation) for 90 positives and 1800 negatives, with a batch of 210 samples requiring only 21 assays. CONCLUSIONS Group testing based on SC is an implementable approach to trinucleotide repeat expansion disorder testing that offers ≥10-fold reduction in assay costs over current single-plex methods.

scholarly journals A Novel FMR1 PCR Method for the Routine Detection of Low Abundance Expanded Alleles and Full Mutations in Fragile X Syndrome

2010 ◽  
Vol 56 (3) ◽  
pp. 399-408 ◽  
Author(s):  
Stela Filipovic-Sadic ◽  
Sachin Sah ◽  
Liangjing Chen ◽  
Julie Krosting ◽  
Edward Sekinger ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Southern Blotting ◽  
Trinucleotide Repeat ◽  
Fragile X ◽  
Clinical Samples ◽  
Full Mutation ◽  
Cgg Repeat ◽  
Specific Pcr ◽  
Cgg Repeats ◽  
Pcr Technology

Abstract Background: Fragile X syndrome (FXS) is a trinucleotide-repeat disease caused by the expansion of CGG sequences in the 5′ untranslated region of the FMR1 (fragile X mental retardation 1) gene. Molecular diagnoses of FXS and other emerging FMR1 disorders typically rely on 2 tests, PCR and Southern blotting; however, performance or throughput limitations of these methods currently constrain routine testing. Methods: We evaluated a novel FMR1 gene–specific PCR technology with DNA templates from 20 cell lines and 146 blinded clinical samples. The CGG repeat number was determined by fragment sizing of PCR amplicons with capillary electrophoresis, and results were compared with those for FMR1 Southern blotting analyses with the same samples. Results: The FMR1 PCR accurately detected full-mutation alleles up to at least 1300 CGG repeats and consisting of >99% GC character. All categories of alleles detected by Southern blotting, including 66 samples with full mutations, were also identified by the FMR1 PCR for each of the 146 clinical samples. Because all full mutation alleles in samples from heterozygous females were detected by the PCR, allele zygosity was reconciled in every case. The PCR reagents also detected a 1% mass fraction of a 940-CGG allele in a background of 99% 23-CGG allele—a roughly 5- fold greater sensitivity than obtained with Southern blotting. Conclusions: The novel PCR technology can accurately categorize the spectrum of FMR1 alleles, including alleles previously considered too large to amplify; reproducibly detect low abundance full mutation alleles; and correctly infer homozygosity in female samples, thus greatly reducing the need for sample reflexing to Southern blotting.

scholarly journals Plasma metabolic profile delineates roles for neurodegeneration, pro-inflammatory damage and mitochondrial dysfunction in the FMR1 premutation

2016 ◽  
Vol 473 (21) ◽  
pp. 3871-3888 ◽  
Author(s):  
Cecilia Giulivi ◽  
Eleonora Napoli ◽  
Flora Tassone ◽  
Julian Halmai ◽  
Randi Hagerman
Keyword(s):  
Mitochondrial Dysfunction ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Fragile X ◽  
Neurological Diseases ◽  
Plasma Metabolites ◽  
Metabolic Pattern ◽  
Fmr1 Premutation ◽  
Cgg Repeats ◽  
Lactate Levels

Carriers of premutation CGG expansions in the fragile X mental retardation 1 (FMR1) gene are at higher risk of developing a late-onset neurodegenerative disorder named Fragile X-associated tremor ataxia syndrome (FXTAS). Given that mitochondrial dysfunction has been identified in fibroblasts, PBMC and brain samples from carriers as well as in animal models of the premutation and that mitochondria are at the center of intermediary metabolism, the aim of the present study was to provide a complete view of the metabolic pattern by uncovering plasma metabolic perturbations in premutation carriers. To this end, metabolic profiles were evaluated in plasma from 23 premutation individuals and 16 age- and sex-matched controls. Among the affected pathways, mitochondrial dysfunction was associated with a Warburg-like shift with increases in lactate levels and altered Krebs' intermediates, neurotransmitters, markers of neurodegeneration and increases in oxidative stress-mediated damage to biomolecules. The number of CGG repeats correlated with a subset of plasma metabolites, which are implicated not only in mitochondrial disorders but also in other neurological diseases, such as Parkinson's, Alzheimer's and Huntington's diseases. For the first time, the identified pathways shed light on disease mechanisms contributing to morbidity of the premutation, with the potential of assessing metabolites in longitudinal studies as indicators of morbidity or disease progression, especially at the early preclinical stages.

Variation of the CGG Repeat in FMR-1 Gene in Normal and Fragile X Chinese Subjects

1997 ◽  
Vol 34 (5) ◽  
pp. 517-520 ◽  
Author(s):  
T A Chen ◽  
X F Lu ◽  
P K Che ◽  
Walter K K Ho
Keyword(s):  
Fragile X Syndrome ◽  
Trinucleotide Repeat ◽  
Fragile X ◽  
Cgg Repeat ◽  
Repeat Size ◽  
Cgg Repeats ◽  
Southern Chinese ◽  
The Usa ◽  
Cytological Features ◽  
Repeat Segment

The fragile X syndrome is believed to be caused by an expansion of a CGG trinucleotide repeat segment in the FMR-1 gene on the fragile X site of the long arm of the X-chromosome. To understand the variation of the CGG repeat in the FMR-1 gene in southern Chinese from the Hong Kong and Guangzhou area, we undertook the present study. A total of 83 normal and three fragile X subjects were examined. In the normal group, 16 distinct alleles, ranging in size from 272 bp to 332 bp with 17 to 37 CGG repeats were detected. A repeat size of 29 was the most frequent. Compared with data collected in the USA, the repeat size observed in this population was somewhat smaller. Whether this discrepancy is due to ethnic difference remains to be determined. The three fragile X patients examined in this study did not have a greatly expanded CGG segment. One of them may be a mosaic with one full and one premutation allele. The other two patients, although having clinical and cytological features of fragile X syndrome, had a CGG repeat size within normal range. To explain this, we infer that the mutation in these patients may be caused by other mechanisms, such as other types of FMR-1 mutation or mutation in another site. It is possible that the expansion of the CGG repeats may not be as frequent a cause of fragile X syndrome in southern Chinese as in other ethnic groups.

Triplet repeats in transcripts: structural insights into RNA toxicity

2012 ◽  
Vol 393 (11) ◽  
pp. 1299-1315 ◽  
Author(s):  
Paulina Galka-Marciniak ◽  
Martyna O. Urbanek ◽  
Wlodzimierz J. Krzyzosiak
Keyword(s):  
Tandem Repeats ◽  
Fragile X ◽  
Genetic Disorders ◽  
Structural Features ◽  
Cag Repeats ◽  
Spinocerebellar Ataxias ◽  
Triplet Repeats ◽  
Triplet Repeat Expansion ◽  
Cgg Repeats ◽  
Ataxia Syndrome

Abstract Tandem repeats of various trinucleotide motifs are frequent entities in transcripts, and RNA structures formed by these sequences depend on the motif type and number of reiterations. The functions performed by normal triplet repeats in transcripts are poorly understood, but abnormally expanded repeats of certain types trigger pathogenesis in several human genetic disorders known as the triplet repeat expansion diseases (TREDs). The diseases caused by expanded non-coding CUG and CGG repeats in transcripts include myotonic dystrophy type 1 and fragile X-associated tremor ataxia syndrome. Another group of disorders in which transcripts containing translated CAG repeats play an auxiliary role in pathogenesis include Huntington’s disease and several spinocerebellar ataxias. In this review, we gathered existing knowledge regarding the structural features of triplet repeats in transcripts and discussed this in the context of various pathogenic mechanisms assigned to toxic RNA repeats. These mechanisms include aberrant alternative splicing, the inhibition of nuclear transport and export, induction of the innate immune response, alteration of a microRNA biogenesis pathway and abnormal activation of an RNA interference pathway. We also provide ideas for future investigations to reveal further mechanisms of pathogenesis directly triggered by mutant RNA repeats in TREDs.

Probing the 14-3-3 Isoform-Specificity Profile of Interactions Stabilized by Fusicoccin A

2020 ◽  
Author(s):  
James Frederich ◽  
Ananya Sengupta ◽  
Josue Liriano ◽  
Ewa A. Bienkiewicz ◽  
Brian G. Miller
Keyword(s):  
Protein Interactions ◽  
Neurological Diseases ◽  
Adapter Proteins ◽  
Protein Protein Interactions ◽  
Specific Expression ◽  
Individual Client ◽  
Isoform Specificity ◽  
Fusicoccin A

Fusicoccin A (FC) is a fungal phytotoxin that stabilizes protein–protein interactions (PPIs) between 14-3-3 adapter proteins and their phosphoprotein interaction partners. In recent years, FC has emerged as an important chemical probe of human 14-3-3 PPIs implicated in cancer and neurological diseases. These previous studies have established the structural requirements for FC-induced stabilization of 14-3-3·client phosphoprotein complexes; however, the effect of different 14-3-3 isoforms on FC activity has not been systematically explored. This is a relevant question for the continued development of FC variants because there are seven distinct isoforms of 14-3-3 in humans. Despite their remarkable sequence and structural similarities, a growing body of experimental evidence supports both tissue-specific expression of 14-3-3 isoforms and isoform-specific functions <i>in vivo</i>. Herein, we report the isoform-specificity profile of FC <i>in vitro</i>using recombinant human 14-3-3 isoforms and a focused library of fluorescein-labeled hexaphosphopeptides mimicking the C-terminal 14-3-3 recognition domains of client phosphoproteins targeted by FC in cell culture. Our results reveal modest isoform preferences for individual client phospholigands and demonstrate that FC differentially stabilizes PPIs involving 14-3-3s. Together, these data provide strong motivation for the development of non-natural FC variants with enhanced selectivity for individual 14-3-3 isoforms.

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