Fragile X full mutation alleles composed of few alleles: Implications for CGG repeat expansion

2007 ◽  
Vol 146A (1) ◽  
pp. 60-65 ◽  
Author(s):  
Sarah L. Nolin ◽  
Xiao-hua Ding ◽  
George E. Houck ◽  
W. Ted Brown ◽  
Carl Dobkin
Keyword(s):  
Fragile X ◽  
Repeat Expansion ◽  
Full Mutation ◽  
Cgg Repeat

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 Cis-acting DNA sequence at a replication origin promotes repeat expansion to fragile X full mutation

2014 ◽  
Vol 206 (5) ◽  
pp. 599-607 ◽  
Author(s):  
Jeannine Gerhardt ◽  
Nikica Zaninovic ◽  
Qiansheng Zhan ◽  
Advaitha Madireddy ◽  
Sarah L. Nolin ◽  
...  
Keyword(s):  
Replication Origin ◽  
Fragile X ◽  
Embryonic Stem ◽  
Repeat Expansion ◽  
Full Mutation ◽  
Single Nucleotide ◽  
Cgg Repeat ◽  
Cis Acting ◽  
Replication Fork Progression ◽  
The Relationship

Fragile X syndrome (FXS) is caused by CGG repeat expansion that leads to FMR1 silencing. Women with a premutation allele are at risk of having a full mutation child with FXS. To investigate the mechanism of repeat expansion, we examined the relationship between a single-nucleotide polymorphism (SNP) variant that is linked to repeat expansion in haplogroup D and a replication origin located ∼53 kb upstream of the repeats. This origin is absent in FXS human embryonic stem cells (hESCs), which have the SNP variant C, but present in the nonaffected hESCs, which have a T variant. The SNP maps directly within the replication origin. Interestingly, premutation hESCs have a replication origin and the T variant similar to nonaffected hESCs. These results suggest that a T/C SNP located at a replication origin could contribute to the inactivation of this replication origin in FXS hESCs, leading to altered replication fork progression through the repeats, which could result in repeat expansion to the FXS full mutation.

scholarly journals Secondary structural choice of DNA and RNA associated with CGG/CCG trinucleotide repeat expansion rationalizes the RNA misprocessing in FXTAS

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yogeeshwar Ajjugal ◽  
Narendar Kolimi ◽  
Thenmalarchelvi Rathinavelan
Keyword(s):  
Rna Binding ◽  
Trinucleotide Repeat ◽  
Rna Binding Proteins ◽  
Fragile X ◽  
Repeat Expansion ◽  
Mobility Shift ◽  
Cgg Repeat ◽  
Dna And Rna ◽  
Structural Choice ◽  
Sense Strand

AbstractCGG tandem repeat expansion in the 5′-untranslated region of the fragile X mental retardation-1 (FMR1) gene leads to unusual nucleic acid conformations, hence causing genetic instabilities. We show that the number of G…G (in CGG repeat) or C…C (in CCG repeat) mismatches (other than A…T, T…A, C…G and G…C canonical base pairs) dictates the secondary structural choice of the sense and antisense strands of the FMR1 gene and their corresponding transcripts in fragile X-associated tremor/ataxia syndrome (FXTAS). The circular dichroism (CD) spectra and electrophoretic mobility shift assay (EMSA) reveal that CGG DNA (sense strand of the FMR1 gene) and its transcript favor a quadruplex structure. CD, EMSA and molecular dynamics (MD) simulations also show that more than four C…C mismatches cannot be accommodated in the RNA duplex consisting of the CCG repeat (antisense transcript); instead, it favors an i-motif conformational intermediate. Such a preference for unusual secondary structures provides a convincing justification for the RNA foci formation due to the sequestration of RNA-binding proteins to the bidirectional transcripts and the repeat-associated non-AUG translation that are observed in FXTAS. The results presented here also suggest that small molecule modulators that can destabilize FMR1 CGG DNA and RNA quadruplex structures could be promising candidates for treating FXTAS.

Learning-disabled Males With a Fragile X CGG Expansion in the Upper Premutation Size Range

PEDIATRICS ◽  
1996 ◽  
Vol 97 (1) ◽  
pp. 122-126
Author(s):  
Randi J. Hagerman ◽  
Louise W. Staley ◽  
Rebecca O'Conner ◽  
Kellie Lugenbeel ◽  
David Nelson ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Size Range ◽  
Cpg Island ◽  
Fragile X ◽  
Learning Disabled ◽  
Full Mutation ◽  
Cgg Repeat ◽  
Responsible Gene ◽  
Repeat Segment

There is a broad spectrum of clinical involvement in both boys and girls affected by fragile X syndrome. Although this disorder is best known as the most common inherited cause of mental retardation, it also can manifest as learning disabilities in individuals with IQs in the broad range of normal. Boys are usually retarded, and girls are usually learning disabled with fragile X syndrome.1 The responsible gene, fragile X mental retardation 1 (FMR1), was isolated in 1991, and the mutation was found to involve expansion of a trinucleotide (CGG) repeat segment. Individuals with fragile X syndrome have a CGG expansion of more than 200 repeats associated with hypermethylation of both the expansion and an adjacent CpG island (full mutation).2,3

scholarly journals FMRP Levels in Human Peripheral Blood Leukocytes Correlates with Intellectual Disability

Diagnostics ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1780
Author(s):  
Mark Roth ◽  
Lucienne Ronco ◽  
Diego Cadavid ◽  
Blythe Durbin-Johnson ◽  
Randi J. Hagerman ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Intellectual Disability ◽  
Peripheral Blood ◽  
Fragile X ◽  
Repeat Expansion ◽  
Repeat Number ◽  
Cgg Repeat ◽  
Fragile X Mental Retardation ◽  
Cgg Repeats ◽  
Fmr1 Mrna

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. FXS is an X-linked, neurodevelopmental disorder caused by a CGG trinucleotide repeat expansion in the 5′ untranslated region (UTR) of the Fragile X Mental Retardation gene, FMR1. Greater than 200 CGG repeats results in epigenetic silencing of the gene leading to the deficiency or absence of Fragile X mental retardation protein (FMRP). The loss of FMRP is considered the root cause of FXS. The relationship between neurological function and FMRP expression in peripheral blood mononuclear cells (PBMCs) has not been well established. Assays to detect and measure FMR1 and FMRP have been described; however, none are sufficiently sensitive, precise, or quantitative to properly characterize the relationships between cognitive ability and CGG repeat number, FMR1 mRNA expression, or FMRP expression measured in PBMCs. To address these limitations, two novel immunoassays were developed and optimized, an electro-chemiluminescence immunoassay and a multiparameter flow cytometry assay. Both assays were performed on PMBCs isolated from 27 study participants with FMR1 CGG repeats ranging from normal to full mutation. After correcting for methylation, a significant positive correlation between CGG repeat number and FMR1 mRNA expression levels and a significant negative correlation between FMRP levels and CGG repeat expansion was observed. Importantly, a high positive correlation was observed between intellectual quotient (IQ) and FMRP expression measured in PBMCs.

scholarly journals Cascade Testing for Fragile X Syndrome in a Rural Setting in Cameroon (Sub-Saharan Africa)

Genes ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 136
Author(s):  
Karen Kengne Kamga ◽  
Séraphin Nguefack ◽  
Khuthala Minka ◽  
Edmond Wonkam Tingang ◽  
Alina Esterhuizen ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Autism Spectrum ◽  
Sub Saharan Africa ◽  
Rural Setting ◽  
Premature Menopause ◽  
Molecular Testing ◽  
Full Mutation ◽  
Cgg Repeat ◽  
Cgg Repeats

Fragile X Syndrome (FXS), an X-linked dominant monogenic condition, is the main genetic cause of intellectual disability (ID) and autism spectrum disorder (ASD). FXS is associated with an expansion of CGG repeat sequence in the Fragile X Mental Retardation gene 1 (FMR1) on chromosome X. Following a neuropediatric assessment of two male siblings who presented with signs of FXS that was confirmed with molecular testing, we provided cascade counselling and testing to the extended family. A total of 46 individuals were tested for FXS; among them, 58.70% (n = 27) were females. The mean age was 9.4 (±5) years for children and 45.9 (±15.9) years for adults. Pedigree analysis suggested that the founder of these families was likely a normal transmitting male. Four out of 19 males with clinical ID were confirmed to have a full mutation for FXS, while 14/27 females had a pathologic CGG expansion (>56 CGG repeats) on one of their X chromosomes. Two women with premature menopause were confirmed of being carriers of premutation (91 and 101 CGG repeats). We also identified maternal alleles (91 and 126 CGG repeats) which expanded to a full mutation in their offspring (>200 CGG repeats). This study is a rare report on FXS from Africa and illustrates the case scenario of implementing genetic medicine for a neurogenetic condition in a rural setting.

scholarly journals Enhanced detection of nucleotide repeat mRNA with hybridization chain reaction

2021 ◽  
Author(s):  
Mary Rebecca Glineburg ◽  
Yuan Zhang ◽  
Elizabeth M Tank ◽  
Sami Barmada ◽  
Peter Todd
Keyword(s):  
Fragile X ◽  
Data Interpretation ◽  
Repeat Expansion ◽  
Hybridization Chain Reaction ◽  
Chain Reaction ◽  
Cgg Repeat ◽  
Hexanucleotide Repeat ◽  
Rna Foci ◽  
Repeat Expansions ◽  
The Impact

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.

scholarly journals Therapeutic Development for CGG Repeat Expansion-Associated Neurodegeneration

2021 ◽  
Vol 15 ◽  
Author(s):  
Keqin Xu ◽  
Yujing Li ◽  
Emily G. Allen ◽  
Peng Jin
Keyword(s):  
Neurological Disorders ◽  
Rna Splicing ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Fragile X ◽  
Repeat Expansion ◽  
Therapeutic Interventions ◽  
Cgg Repeat ◽  
Associated Diseases ◽  
Novel Therapeutic Strategies

Non-coding repeat expansions, such as CGG, GGC, CUG, CCUG, and GGGGCC, have been shown to be involved in many human diseases, particularly neurological disorders. Of the diverse pathogenic mechanisms proposed in these neurodegenerative diseases, dysregulated RNA metabolism has emerged as an important contributor. Expanded repeat RNAs that form particular structures aggregate to form RNA foci, sequestering various RNA binding proteins and consequently altering RNA splicing, transport, and other downstream biological processes. One of these repeat expansion-associated diseases, fragile X-associated tremor/ataxia syndrome (FXTAS), is caused by a CGG repeat expansion in the 5’UTR region of the fragile X mental retardation 1 (FMR1) gene. Moreover, recent studies have revealed abnormal GGC repeat expansion within the 5’UTR region of the NOTCH2NLC gene in both essential tremor (ET) and neuronal intranuclear inclusion disease (NIID). These CGG repeat expansion-associated diseases share genetic, pathological, and clinical features. Identification of the similarities at the molecular level could lead to a better understanding of the disease mechanisms as well as developing novel therapeutic strategies. Here, we highlight our current understanding of the molecular pathogenesis of CGG repeat expansion-associated diseases and discuss potential therapeutic interventions for these neurological disorders.

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