Human genes containing polymorphic trinucleotide repeats

Riggins, Gregory J.; Lokey, Laurie K.; Chastain, Jane L.; Leiner, Harold A.; Sherman, Stephanie L.; Wilkinson, Keith D.; Warren, Stephen T.

doi:10.1038/ng1192-186

Cited by 149 publications

(67 citation statements)

References 42 publications

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“…Structural variants are modifications in an organism's chromosome due to insertions, deletions, inversions, translocations and duplications commonly referred to as copy -number variants (CNV's) which are usually >1Kb in length [68]. If present at >1% in a population a CNV may be referred to as copy number polymorphism (CNP).…”

Section: Structural Variantsmentioning

confidence: 99%

Non-coding DNA – a brief review

2017

J App Biol Biotech

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In addition to the coding segments, genomes of all organisms are made of several highly conserved nonprotein coding regions. Biochemical analysis by isolating non-coding regions from cells, tissues or whole organism studies are powerful tools for their identification. In lieu of this, identifying and annotating these regions using comparative and functional genomics approaches should be a high priority. Understanding and identifying their location and what these segments are composed of would pave way for functional annotation. Large scale functional genomics approaches help to identify novel genes and allow to hypothesize its in vivo function systematically in turn aid in annotating the conserved regions obtained from comparative genomics at the sequence level. In this review, we survey all non-coding regions, their importance and their functional roles newly discovered.

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Section: Structural Variantsmentioning

confidence: 99%

Non-coding DNA – a brief review

2017

J App Biol Biotech

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“…4,5 GSTs activity involves in the pathogenesis of DM1 because it contains polymorphic trinucleotide repeat. 6 Human GSTs represent a large and diverse super family of enzymes, with at least 13 GST enzymes belonging to five different families: mu, theta, alpha, pi, and gamma. The GSTM1 & GSTM3, GSTT1 and GSTP1 belong to the GSTmu, GSTtheta, and GSTpi categories of enzymes respectively.…”

Section: Introductionmentioning

confidence: 99%

GST Polymorphisms and GST Enzyme Activity in Type 1 Myotonic Dystrophy

Agarwal¹

2015

JIG

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chain reaction; +/+/+, gstm1, gst1 and gstm3 present; -/-/-, gstm1, gstt1 and gstm3 absent; ile/val and ile/ile=heterozygous and homozygous status of GSTP1 IntroductionMyotonic dystrophy (DM) is an autosomal dominant, multisystem trinucleotide repeat disorder. Myotonic dystrophy is clinically heterogeneous and at the molecular level at least two types can be distinguished: DM type 1 (DM1; Steinert disease) and DM type 2 (DM2; proximal myotonic myopathy (PROMM) or Ricker syndrome). DM1 is the most common form of muscular dystrophy in adults with an estimated incidence of 1:8000.1 Two different mutations are responsible for DM: DM1 (OMIM #160900) is caused by a (CTG)n repeat expansion in the 3'-untranslated region of the DMPK gene located within chromosome band 19ql3.3 2,3 while DM2 (OMIM #602688) is caused by a large (CCTG)n repeat expansion in intron l of the CNBP gene at chromosome 3q21. 4,5 GSTs activity involves in the pathogenesis of DM1 because it contains polymorphic trinucleotide repeat.6 Human GSTs represent a large and diverse super family of enzymes, with at least 13 GST enzymes belonging to five different families: mu, theta, alpha, pi, and gamma. The GSTM1 & GSTM3, GSTT1 and GSTP1 belong to the GSTmu, GSTtheta, and GSTpi categories of enzymes respectively. Glutathione S-transferases (GSTs) are phase II detoxifying enzymes that catalyze a variety of reduced glutathione-dependent reactions with electrophilic substrates, including active metabolites of carcinogens. 7 In particular, GSTM1, GSTM3, GSTP1 and GSTT1 are involved in detoxification of active metabolites of several potential carcinogens such as benzo [a]pyrene and other polycyclic aromatic hydrocarbons, monohalomethanes and ethylene oxide.7-9 It also play an important role in the functioning of antioxidant defences through reactive oxygen species (ROS) metabolism, in the repairing of damaged ROS and in the detoxification of several xenobiotics. 7,10 The absence of GSTT1 and GSTM1 enzyme activities is caused by homozygous deletion of the respective genes (null genotypes). 11,12 In the GSTM3 gene, the GSTM3*A wild-type allele and the GSTM3*B variant allele have been described. 8 GSTM3*B contains a recognition motif for the YY1 transcription factor, which has been postulated to regulate gene expression. 13 It was suggested that GSTM3*A and GSTM3*B are expressed at different levels and could therefore confer different efficiencies in the metabolism of carcinogens and toxic compounds.14 In the GSTP1 gene, 2 variant alleles, GSTP1*B and GSTP1*C, have been detected in addition to the wild-type allele GSTP1*A.9 Both variant alleles have an A-to-G transition at nucleotide 313, causing a change of isoleucine (Ile) to valine (Val) at codon 105. The specific activity and affinity for electrophilic substrates is altered in the Val variant.9 It is therefore plausible that hereditary differences in the activities of these enzymes, due to genetic polymorphisms. 8,9,11,12 Different GSTs polymorphism has been studied in various malignancies.15-18 However, there ...

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“…Trinucleotide disease genes identified to date contain CAG/CTG, CCG/ CGG, GAA/TTC (see Reddy and Housman 1997) and GCG/CGC (Brais 1998). It is possible that expansions resulting in disease may occur in other motifs as a number of genes containing short but polymorphic triplet repeats have been described (Riggins et al 1992). We have focused on optimizing detection of the most commonly occurring expansion (CAG/CTG) (Riggins et al 1992;Lindblad et al 1994).…”

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confidence: 99%

“…It is possible that expansions resulting in disease may occur in other motifs as a number of genes containing short but polymorphic triplet repeats have been described (Riggins et al 1992). We have focused on optimizing detection of the most commonly occurring expansion (CAG/CTG) (Riggins et al 1992;Lindblad et al 1994).The repeat expansion detection (RED) (Schalling et al 1993) technique was developed to make possible the identification of repeat expansions from total genomic DNA without knowledge of flanking sequences. RED has been used to detect expansions in genomic DNA from patients with the trinucleotide diseases myotonic dystrophy (Schalling et al 1993), Machado-Joseph disease (Lindblad et al 1996), and spinocerebellar ataxia type 7 (Lindblad et al 1996).…”

mentioning

confidence: 99%

Multivariate Analysis of Factors Influencing Repeat Expansion Detection

Zander¹,

Thelaus²,

Lindblad³

et al. 1998

Genome Res.

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Repeat expansion detection (RED) is a powerful tool for detection of expanded repeat sequences in the genome. In RED, DNA serves as a template for a repeat-specific oligonucleotide. A thermostable ligase is used to ligate oligonucleotides that have annealed at adjacent positions, creating multimers in a thermal cycling procedure. The products are visualized after gel electrophoresis, transfered to a membrane and subsequently hybridized. Multiple linear regression (MLR) and partial least square (PLS) techniques were used to reveal the most influential factors in the amplification reaction and to identify possible interacting factors. Ligation temperature proved to be the most important factor in the reaction: Temperatures far below the melting point of the oligonucleotide increased the yield considerably. Higher cycle number resulted in a continuous rise in intensity, indicating that the ligase remained active even after 700 cycles or 12 hr of cycling. In addition, the concentration of ligase was found to be important. Using optimal parameters, a 5.5-and 3.2-fold increase in the yield of 180-and 360-nucleotide products respectively was obtained. The improved sensitivity makes the method more robust and facilitates detection of repeat expansions. This improvement may be particularly useful in development of RED for diagnostic purposes as well as for nonradioactive detection of RED products. Based on these results, a new protocol for the RED method was developed taking into account the risk of introducing artifacts with increased enzyme concentrations and lowered annealing temperatures.In the past few years, expansions of trinucleotide repeats have provided a molecular explanation for a number of genetic disorders, notably myotonic dystrophy (Aslanidis et al. 1992;Fu et al. 1992;Brook et al. 1992) and Huntington's disease (Huntington's Disease Collaborative Research Group 1993) as well as several others (for review, see Lindblad and Schalling 1996;Reddy and Housman 1997). A common feature of these disorders is that they cause dysfunction of the central nervous system, with strong phenotypic variability even within families. Increasingly severe phenotypes are observed in subsequent generations, a phenomenon referred to as genetic anticipation. There is evidence for genetic anticipation in other disorders including bipolar affective illness (McInnis et al. 1993;Nylander et al. 1994;Grigoroiu-Serbanescu et al. 1997), schizophrenia (Asherson et al. 1994;Bassett and Honer 1994;Thibaut et al. 1995), and familial hereditary tremor (Chritchely et al. 1949;Jankovic et al. 1997). It is possible that a number of these disorders are caused by genes containing repeat sequences that may expand and lead to dysfunction. Trinucleotide disease genes identified to date contain CAG/CTG, CCG/ CGG, GAA/TTC (see Reddy and Housman 1997) and GCG/CGC (Brais 1998). It is possible that expansions resulting in disease may occur in other motifs as a number of genes containing short but polymorphic triplet repeats have been described (Riggins et...

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Human genes containing polymorphic trinucleotide repeats

Cited by 149 publications

References 42 publications

Non-coding DNA – a brief review

Non-coding DNA – a brief review

GST Polymorphisms and GST Enzyme Activity in Type 1 Myotonic Dystrophy

Multivariate Analysis of Factors Influencing Repeat Expansion Detection

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