204. Isolation of CAG repeat containing genes from human placenta and decidua

2005 ◽  
Vol 17 (9) ◽  
pp. 77
Author(s):  
K. A. Freed ◽  
S. P. Brennecke ◽  
E. K. Moses
Keyword(s):  
Mutation Rate ◽  
Dna Sequences ◽  
Human Placenta ◽  
Trinucleotide Repeat ◽  
Normal Population ◽  
Repeat Expansion ◽  
Cag Repeat ◽  
High Mutation Rate ◽  
Strong Negative Selection ◽  
Expansion Mutation

Pre-eclampsia is a serious disorder of pregnancy that manifests clinically in the mother as new-onset hypertension and proteinuria. Although the precise cause remains unknown, the placenta and the decidua play a fundamental role. The worldwide incidence of pre-eclampsia is 2–5% and such a high incidence, in the face of strong negative selection, suggests that the gene(s) involved have a selective advantage and/or a high mutation rate. One class of genetic diseases that involve a high mutation rate are the trinucleotide repeat expansion diseases. In these diseases repeated trinucleotide DNA sequences within specific genes multiply or expand up to 1000-fold. The result of this gene expansion/mutation is altered gene function that confers genetic susceptibility. Thus, the overall objective of this study was to determine whether there is an association between a trinucleotide (CAG) repeat expansion and pre-eclampsia. The specific aim of this study was to isolate CAG repeat containing genes from human placenta and decidua. An adaptation of the mRNA differential display technique and traditional cDNA library screening was used. In total, 72 placental and 51 decidual sequences were analyzed using the BLAST nucleotide comparison program. Five cDNAs were analyzed further. The unique sequences surrounding the CAG repeat regions of these five genes will be used to generate primers to ascertain if any of these repeat DNA sequences vary in number in the normal population. If polymorphic genes are identified, the primers will be used on pre-eclamptic pedigrees to determine if pre-eclampsia is associated with a repeat expansion mutation.

scholarly journals Genome Wide Screening of CAG Trinucleotide Repeat Lengths in Breast Cancer

2006 ◽  
Vol 22 (5-6) ◽  
pp. 343-349 ◽  
Author(s):  
Hamdi Jarjanazi ◽  
Hong Li ◽  
Irene L. Andrulis ◽  
Hilmi Ozcelik
Keyword(s):  
Breast Cancer ◽  
Trinucleotide Repeat ◽  
Neuromuscular Disorders ◽  
Repeat Expansion ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Healthy Population ◽  
Genome Wide ◽  
A Genome ◽  
Population Controls

Trinucleotide repeat sequences are widely present in the human genome. The expansion of CAG repeats have been studied very extensively, and shown to be the causative mechanism of more than 40 neuromuscular and neurodegenerative diseases. In the present study, we performed a genome wide screening of CAG repeat expansions in non-neoplastic tissues of 212 breast cancer cases and 196 healthy population controls using the Repeat Expansion Detection (RED) method. Distribution of CAG repeat lengths in cases was not significantly different from controls. However, dramatically expanded CAG repeats were detected in 2.4% (n= 5) of breast cancer cases where no repeats of similar size were detected in any of the healthy population controls. Although this trend shows only borderline significance (p= 0.06), this finding suggests a potential involvement of CAG repeat expansion in breast cancer susceptibility. These repeats may potentially affect the function of cancer predisposition genes, with a similar mechanism as in neurodegenerative and neuromuscular disorders.

scholarly journals Comparative (Computational) Analysis of the DNA Methylation Status of Trinucleotide Repeat Expansion Diseases

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Mohammadmersad Ghorbani ◽  
Simon J. E. Taylor ◽  
Mark A. Pook ◽  
Annette Payne
Keyword(s):  
Dna Methylation ◽  
Dna Sequences ◽  
Computational Analysis ◽  
Trinucleotide Repeat ◽  
De Novo ◽  
Fragile X ◽  
Methylation Status ◽  
Repeat Expansion ◽  
Type I ◽  
Trinucleotide Repeat Diseases

Previous studies have examined DNA methylation in different trinucleotide repeat diseases. We have combined this data and used a pattern searching algorithm to identify motifs in the DNA surrounding aberrantly methylated CpGs found in the DNA of patients with one of the three trinucleotide repeat (TNR) expansion diseases: fragile X syndrome (FRAXA), myotonic dystrophy type I (DM1), or Friedreich’s ataxia (FRDA). We examined sequences surrounding both the variably methylated (VM) CpGs, which are hypermethylated in patients compared with unaffected controls, and the nonvariably methylated CpGs which remain either always methylated (AM) or never methylated (NM) in both patients and controls. Using the J48 algorithm of WEKA analysis, we identified that two patterns are all that is necessary to classify our three regions CCGG* which is found in VM and not in AM regions and AATT* which distinguished between NM and VM + AM using proportional frequency. Furthermore, comparing our software with MEME software, we have demonstrated that our software identifies more patterns than MEME in these short DNA sequences. Thus, we present evidence that the DNA sequence surrounding CpG can influence its susceptibility to bede novomethylated in a disease state associated with a trinucleotide repeat.

scholarly journals The Role of the Immune System in Triplet Repeat Expansion Diseases

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Marta Olejniczak ◽  
Martyna O. Urbanek ◽  
Wlodzimierz J. Krzyzosiak
Keyword(s):  
Immune System ◽  
Trinucleotide Repeat ◽  
Inflammatory Responses ◽  
Neurological Diseases ◽  
Repeat Expansion ◽  
Cag Repeat ◽  
Triplet Repeat ◽  
Triplet Repeat Expansion ◽  
Polyglutamine Disorders ◽  
Intracellular Aggregates

Trinucleotide repeat expansion disorders (TREDs) are a group of dominantly inherited neurological diseases caused by the expansion of unstable repeats in specific regions of the associated genes. Expansion of CAG repeat tracts in translated regions of the respective genes results in polyglutamine- (polyQ-) rich proteins that form intracellular aggregates that affect numerous cellular activities. Recent evidence suggests the involvement of an RNA toxicity component in polyQ expansion disorders, thus increasing the complexity of the pathogenic processes. Neurodegeneration, accompanied by reactive gliosis and astrocytosis is the common feature of most TREDs, which may suggest involvement of inflammation in pathogenesis. Indeed, a number of immune response markers have been observed in the blood and CNS of patients and mouse models, and the activation of these markers was even observed in the premanifest stage of the disease. Although inflammation is not an initiating factor of TREDs, growing evidence indicates that inflammatory responses involving astrocytes, microglia, and the peripheral immune system may contribute to disease progression. Herein, we review the involvement of the immune system in the pathogenesis of triplet repeat expansion diseases, with particular emphasis on polyglutamine disorders. We also present various therapeutic approaches targeting the dysregulated inflammation pathways in these diseases.

scholarly journals Huntington disease update: new insights into the role of repeat instability in disease pathogenesis

2021 ◽  
Vol 33 (4) ◽  
pp. 293-300
Author(s):  
Larissa Arning ◽  
Huu Phuc Nguyen
Keyword(s):  
Disease Progression ◽  
Dna Sequences ◽  
Huntington Disease ◽  
Trinucleotide Repeat ◽  
Age At Onset ◽  
Repeat Sequence ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Causative Mutation ◽  
Cognitive Disability

Abstract The causative mutation for Huntington disease (HD), an expanded trinucleotide repeat sequence in the first exon of the huntingtin gene (HTT) is naturally polymorphic and inevitably associated with disease symptoms above 39 CAG repeats. Although symptomatic medical therapies for HD can improve the motor and non-motor symptoms for affected patients, these drugs do not stop the ongoing neurodegeneration and progression of the disease, which results in severe motor and cognitive disability and death. To date, there is still an urgent need for the development of effective disease‐modifying therapies to slow or even stop the progression of HD. The increasing ability to intervene directly at the roots of the disease, namely HTT transcription and translation of its mRNA, makes it necessary to understand the pathogenesis of HD as precisely as possible. In addition to the long-postulated toxicity of the polyglutamine-expanded mutant HTT protein, there is increasing evidence that the CAG repeat-containing RNA might also be directly involved in toxicity. Recent studies have identified cis- (DNA repair genes) and trans- (loss/duplication of CAA interruption) acting variants as major modifiers of age at onset (AO) and disease progression. More and more extensive data indicate that somatic instability functions as a driver for AO as well as disease progression and severity, not only in HD but also in other polyglutamine diseases. Thus, somatic expansions of repetitive DNA sequences may be essential to promote respective repeat lengths to reach a threshold leading to the overt neurodegenerative symptoms of trinucleotide diseases. These findings support somatic expansion as a potential therapeutic target in HD and related repeat expansion disorders.

scholarly journals Disrupting the Molecular Pathway in Myotonic Dystrophy

2021 ◽  
Vol 22 (24) ◽  
pp. 13225
Author(s):  
Xiaomeng Xing ◽  
Anjani Kumari ◽  
Jake Brown ◽  
John David Brook
Keyword(s):  
Muscular Dystrophy ◽  
Myotonic Dystrophy ◽  
Trinucleotide Repeat ◽  
Repeat Expansion ◽  
Trinucleotide Repeat Expansion ◽  
Molecular Pathway ◽  
Repeat Expansion Mutation ◽  
Expansion Mutation

Myotonic dystrophy is the most common muscular dystrophy in adults. It consists of two forms: type 1 (DM1) and type 2 (DM2). DM1 is associated with a trinucleotide repeat expansion mutation, which is transcribed but not translated into protein. The mutant RNA remains in the nucleus, which leads to a series of downstream abnormalities. DM1 is widely considered to be an RNA-based disorder. Thus, we consider three areas of the RNA pathway that may offer targeting opportunities to disrupt the production, stability, and degradation of the mutant RNA.

scholarly journals Screening A Trinucleotide Repeat Expansion: How precise PCR can be?

2019 ◽  
Vol 3 (3) ◽  
pp. 34-40
Author(s):  
Ziske Maritska ◽  
Baharudin Baharudin ◽  
Ardy Santosa ◽  
Ching Leng Kee ◽  
Tan Yue Ming ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Trinucleotide Repeat ◽  
Repeat Expansion ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Chain Reaction ◽  
Trinucleotide Repeat Expansion ◽  
Pcr Method ◽  
The Mean ◽  
Polymerase Chain

ABSTRACT Background. Trinucleotide Repeat Expansion (TRE) in human DNA could lead to various diseases. An expanded CAG repeat (>31 or 37 repeats, depends on the ethnicity) in Androgen Receptor gene is suggested to be associated with the occurrence of isolated hypospadias. In an effort to identify the exact numbers of repeats, sequencing has been the most favored method to be conducted despite its cost. Objective. This study wished to investigate the possibilities of using Polymerase Chain Reaction (PCR) method to screen expanded repeats in isolated hypospadias, as one of the TRE diseases. Materials and Methods. Numbers of CAG repeat in twelve hypospadias patients and one normal male was first predicted from the visualization of PCR products in 3% agarose gel electrophoreses with 20 bp ladder marker before it was finally sequenced. Results. Two samples gave the same exact result, while the rest showed a range of 1-11 bp differences. Statistically, there was a significant difference between the mean of CAG repeats from PCR method (M=26.1667, SD=6.71272) and the mean of CAG repeats from sequencing (M=23.75, SD=5.70685); t(11)= 4.570, p=0.001. Furthermore, the sensitivity of PCR was 100% and the specificity was 83.33%. Conclusion. It can be concluded that PCR method could be used as a screening method in identifying TRE with large numbers of repeats. However, PCR in TRE disease with small numbers of expanded repeats needs to be followed by sequencing in order to obtain the exact numbers of repeats.   Keywords: Trinucleotide Repeat Expansion, Polymerase Chain Reaction, Sequencing, Isolated Hypospadias

Trinucleotide repeat expansion mutation and preeclampsia

2000 ◽  
Vol 28 (5) ◽  
pp. A300-A300
Author(s):  
K. A. Freed ◽  
E. K. Moses ◽  
D. W. Cooper ◽  
S. P. Brennecke
Keyword(s):  
Trinucleotide Repeat ◽  
Repeat Expansion ◽  
Trinucleotide Repeat Expansion ◽  
Repeat Expansion Mutation ◽  
Expansion Mutation
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