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At least 19 recordsLinked to original sources
PubMed2002

Conformational energetics of stable and metastable states formed by DNA triplet repeat oligonucleotides: implications for triplet expansion diseases.

We have embedded the hexameric triplet repeats (CAG)(6) and (CTG)(6) between two (GC)(3) domains to produce two 30-mer hairpins with the sequences d[(GC)(3)(CAG)(6)(GC)(3)] and d[(GC)(3)(CTG)(6)(GC)(3)]. This construct reduces the conformational space available to these repetitive DNA sequences. We find that the (CAG)(6) and (CTG)(6) repeats form stable, ordered, single-stranded structures. These structures are stabilized at 62 degrees C by an average enthalpy per base of 1.38 kcal.mol(-1) for the CAG triplet and 2.87 kcal.mol(-1) for the CTG triplet, while being entropically destabilized by 3.50 cal.K(-1).mol(-1) for the CAG triplet and 7.6 cal.K(-1).mol(-1) for the CTG triplet. Remarkably, these values correspond, respectively, to 1/3 (for CAG) and 2/3 (for CTG) of the enthalpy and entropy per base values associated with Watson-Crick base pairs. We show that the presence of the loop structure kinetically inhibits duplex formation from the two complementary 30-mer hairpins, even though the duplex is the thermodynamically more stable state. Duplex formation, however, does occur at elevated temperatures. We propose that this thermally induced formation of a more stable duplex results from thermal disruption of the single-stranded order, thereby allowing the complementary domains to associate (perhaps via "kissing hairpins"). Our melting profiles show that, once duplex formation has occurred, the hairpin intermediate state cannot be reformed, consistent with our interpretation of kinetically trapped hairpin structures. The duplex formed by the two complementary oligonucleotides does not have any unusual optical or thermodynamic properties. By contrast, the very stable structures formed by the individual single-stranded triplet repeat sequences are thermally and thermodynamically unusual. We discuss this stable, triplet repeat, single-stranded structure and its interconversion with duplex in terms of triplet expansion diseases.

Base Sequence↗
PubMed1998

NGG-triplet repeats form similar intrastrand structures: implications for the triplet expansion diseases.

Tandem repeats of certain trinucleotides show extensive intergenerational instability in humans that is associated with a class of genetic disorders known as the Triplet Expansion Diseases. This instability is thought to be a consequence of the formation of intrastrand structures, including hairpins, triplexes and tetraplexes, by the tandem repeats. I show here that CGG-repeats which are associated with this group of diseases, and AGG- and TGG-repeats which are not currently known to be, form several intrastrand structures including tetraplexes. In all cases the tetraplexes have the same overall conformation in which all the G residues are involved in G4-tetrads. CGG-repeats also form stable hairpins, but AGG- and TGG-repeats do not form hairpins of comparable stability. However, since tetraplexes can be thought of as folded hairpins, many of the properties ascribed to disease-associated triplets that form hairpins, may apply to these sequences as well. The fact that AGG- and TGG-repeats are not currently associated with any triplet expansion disease suggests either that the ability to adopt an intrastrand folded structure is not sufficient for expansion, or that other diseases associated with such triplets might remain to be identified.

Base Sequence↗
PubMed2026

Two new cases of fragile X syndrome without CGG triplet expansion. Clinical-molecular characterization and review of the literature.

Fragile X syndrome (FXS) is classically caused by CGG repeat expansion in the FMR1 gene leading to gene silencing. We describe two unrelated patients with clinical features consistent with FXS but harbouring distinct molecular mechanisms. The first patient had a pathogenic intronic variant in FMR1, predicted to impair protein function, and no repeat expansion. The second patient carried a complete deletion of the FMR1 gene, resulting in loss of gene expression. Both individuals presented with developmental delay, intellectual disability, and behavioural manifestations typical of FXS. These cases expand the causal heterogeneity underlying a clinically recognizable phenotype. They reinforce the concept that comprehensive molecular testing beyond repeat expansion analysis is mandatory in individuals with a strong clinical suspicion of FXS, in absence of a typical CGG triplet expansion.

Child, Preschool↗
PubMed2002

Hairpin formation in Friedreich's ataxia triplet repeat expansion.

Triplet repeat tracts occur throughout the human genome. Expansions of a (GAA)(n)/(TTC)(n) repeat tract during its transmission from parent to child are tightly associated with the occurrence of Friedreich's ataxia. Evidence supports DNA slippage during DNA replication as the cause of the expansions. DNA slippage results in single-stranded expansion intermediates. Evidence has accumulated that predicts that hairpin structures protect from DNA repair the expansion intermediates of all of the disease-associated repeats except for those of Friedreich's ataxia. How the latter repeat expansions avoid repair remains a mystery because (GAA)(n) and (TTC)(n) repeats are reported not to self-anneal. To characterize the Friedreich's ataxia intermediates, we generated massive expansions of (GAA)(n) and (TTC)(n) during DNA replication in vitro using human polymerase beta and the Klenow fragment of Escherichia coli polymerase I. Electron microscopy, endonuclease cleavage, and DNA sequencing of the expansion products demonstrate, for the first time, the occurrence of large and growing (GAA)(n) and (TTC)(n) hairpins during DNA synthesis. The results provide unifying evidence that predicts that hairpin formation during DNA synthesis mediates all of the disease-associated, triplet repeat expansions.

DNA↗
PubMed1995

Type IV hyperlipoproteinemia and moderate instability of CAG triplet expansion in the androgen-receptor gene. Lipid, sex hormone and molecular study in a Chinese family with Kennedy-Alter-Sung disease.

Kennedy-Alter-Sung (KAS) disease in a hereditary lower motor neuron disease. In this study, we investigate 2 KAS patients presenting with progressive muscle weakness and wasting, action tremor, perioral fasciculation and gynecomastia. Three carriers and 5 healthy members from this 3-generation KAS Chinese family and 60 normal Chinese controls were included in this study. Hormone studies revealed normal serum level in thyrotropin, prolactin, testosterone, leuteinizing hormone, follicle stimulating hormone, and estradiol. Lipid study disclosed type IV hyperlipoproteinemia in 2 KAS patients and 3 healthy members. Molecular studies revealed that the number of CAG triplet repeats in the first exon of androgen receptor gene of the normal allele is in the range of 15-19 and 12-25 in this family and normal controls, respectively. However, the number of CAG repeat of androgen receptor gene were unstable in the mutant alleles with a range of 41-45 and increased from generation to generation (genomic anticipation) in the 2 KAS patients and 3 female carriers. We conclude that the CAG triplet repeats in mutant allele were unstable in the family with the KAS disease. Furthermore, type IV hyperlipoproteinemia may be a co-transmitted syndrome in the family with KAS disease.

Alleles↗
PubMed1997

Sequence fossils, triplet expansion, and reconstruction of earliest codons.

mRNA sequences are known to carry a hidden periodical pattern (GCU)n, which may be considered a remnant of sequence organization of mRNA early in its evolution, dominated by codons for alanine and their point mutation derivatives. A similar pattern is characteristic of the master (consensus) tRNA sequence derived in 1981 by Eigen and Winkler-Oswatitsch. The master tRNA sequence is thought to represent one of the earliest mRNA. From analysis of literature and from our own calculations presented in this work, the (GCU)n pattern appears to be the most expandable in the norm and in disease. The speculation is put forward that (GCU)n and polyalanine have been key players at the beginning of the triplet code, and the first codons, apart from the GCU triplet, were point change derivatives of the generic triplet GCU, coding for amino acids present in the early prebiotic-biotic environment. The set of the earliest amino acids is derived on the basis of structural simplicity, presence in imitated prebiotic conditions and involvement with class II aminoacyl-tRNA synthetases. The set consists of six amino acids: Ala, Asp, Gly, Pro, Ser and Thr. All these amino acids are, indeed, encoded by the GCU triplet and its derivatives, as predicted. Thus, the pairs GCN (Ala), GAU (Asp), GGU (Gly), CCU (Pro), UCU (Ser) and ACU (Thr) can be viewed as an early triplet code.

Codon↗
PubMed2001

Unusual triplet expansion associated with neurogenic changes in a family with oculopharyngeal muscular dystrophy.

The occasional observation of neurogenic features in oculopharyngeal muscular dystrophy (OPMD) is unclear both in nosological and in etiological respects. Studies are reported here of a family with autosomal-dominant OPMD involving seven members over three generations. In three of them muscle biopsies were performed. Two of the patients (a 45-year-old sister and a 57-year-old brother of the third generation) were studied in more detail and, in addition to the typical changes of OPMD, showed a neurogenic component both by electrophysiology and morphology. Molecular genetic investigations revealed a repeat unit of (GCG/GCA)13 in the first exon of the poly(A)binding-protein2 gene in both siblings. A possible association of this unusually long triplet repeat extension with the atypical phenotype is considered and has to be verified in other cases.

Biopsy↗
PubMed1999

[Disease picture of myotonic muscular dystrophy in patients with large CTG triplet expansion].

Myotonic dystrophy is an autosomal dominant multisystem disorder involving muscle, brain, heart, eyes, and endocrine organs. The underlying mutation is an expanding trinucleotide CTG repeat in the 3'prime untranslated region of a serine-threonine kinase gene on chromosome 19q. A statistical correlation exists between the CTG copy number and the severity of the disease. Infants with severe congenital myotonic dystrophy have been shown to have on average a greater amplification of the CTG repeat than is seen in the non-congenital myotonic dystrophy population. However, not all patients with many CTG copies develop congenital myotonic dystrophy. We present 13 patients with more than 1500 CTG trinucleotide repeats and show their variable clinical course.

Adolescent↗
PubMed2000

Coevolution of HLA-B and PERB11.1 (MICA): significance of independent triplet expansion within the transmembrane region of PERB11.1 (MICA).

Several highly polymorphic sequences are present in the beta block of the MHC, especially HLA-B, HLA-C, PERB11.1 (MICA), and PERB11.2 (MICB). It is now apparent that the polymorphism of PERB11.1 is of the same order as that of HLA-A, -B, and -C and it has been suggested that PERB11 could explain some of the disease associations previously attributed to HLA-B. Phylogenetic analysis of PERB11 alpha-domain sequences demonstrates relationships with HLA-B cross-reactive serogroups. In contrast, the transmembrane polymorphisms do not appear to be associated with either PERB11 or HLA-B. These data indicate that PERB11 and HLA-B have evolved in concert from their common ancestors and that the transmembrane polymorphisms have arisen independently and more recently. MHC disease associations will need to be reviewed in the light of mechanisms such as receptor binding and signaling.

Base Sequence↗
PubMed1998

Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract.

The neurodegenerative diseases Huntington disease, dentatorubropallidoluysian atrophy, spinocerebellar atrophy type 3, and spinal bulbar muscular atrophy are caused by expansion of a polyglutamine tract within their respective gene products. There is increasing evidence that generation of truncated proteins containing an expanded polyglutamine tract may be a key step in the pathogenesis of these disorders. We now report that, similar to huntingtin, atrophin-1, ataxin-3, and the androgen receptor are cleaved in apoptotic extracts. Furthermore, each of these proteins is cleaved by one or more purified caspases, cysteine proteases involved in apoptotic death. The CAG length does not modulate susceptibility to cleavage of any of the full-length proteins. Our results suggest that by generation of truncated polyglutamine-containing proteins, caspase cleavage may represent a common step in the pathogenesis of each of these neurodegenerative diseases.

Amino Acid Sequence↗
PubMed1997

Molecular genetics of triplet repeats: unstable expansion of triplet repeats as a new mechanism for neurodegenerative diseases.

Expansion of trinucleotide repeats has been identified as a common mechanism of hereditary neurodegenerative diseases including spinal and bulbar muscular atrophy (SBMA), Huntington's disease, dentatorubral-pallidoluysian atrophy (DRPLA), Machado-Joseph disease (MJD), fragile X syndrome, myotonic dystrophy and Friedreich's ataxia. These diseases share unique features, which are difficult to explain based on Mendelian inheritance. These unique clinical genetic features include genetic anticipation and a broad spectrum of clinical presentations, which have been shown to be associated with the instability of the trinucleotide repeats. Recent studies suggest that gene products with expanded polyglutamine tracts may be toxic to neuronal cells, and the mechanisms of neurotoxicity should be thoroughly investigated. To develop therapeutic measures, creation of animal models or cell culture systems for the investigation of neurotoxicity will be indispensable.

Age of Onset↗
PubMed2003

Analysis of human flap endonuclease 1 mutants reveals a mechanism to prevent triplet repeat expansion.

Flap endonuclease 1 (FEN1), involved in the joining of Okazaki fragments, has been proposed to restrain DNA repeat sequence expansion, a process associated with aging and disease. Here we analyze properties of human FEN1 having mutations at two conserved glycines (G66S and G242D) causing defects in nuclease activity. Introduction of these mutants into yeast led to sequence expansions. Reconstituting triplet repeat expansion in vitro, we previously found that DNA ligase I promotes expansion, but FEN1 prevents the ligation that forms expanded products. Here we show that among the intermediates that could generate sequence expansion, a bubble is necessary for ligation to produce the expansion product. Severe exonuclease defects in the mutant FEN1 suggested that the inability to degrade bubbles exonucleolytically leads to expansion. However, even wild type FEN1 exonuclease cannot compete with DNA ligase I to degrade a bubble structure before it can be ligated. Instead, we propose that FEN1 suppresses sequence expansion by degrading flaps that equilibrate with bubbles, thereby reducing bubble concentration. In this way FEN1 employs endonuclease rather than exonuclease to prevent expansions. A model is presented describing the roles of DNA structure, DNA ligase I, and FEN1 in sequence expansion.

Base Sequence↗
PubMed1995

Triplet repeat expansion in myotonic dystrophy alters the adjacent chromatin structure.

Myotonic dystrophy is caused by an expansion of a CTG triplet repeat sequence in the 3' noncoding region of a protein kinase gene, yet the mechanism by which the triplet repeat expansion causes disease remains unknown. This report demonstrates that a DNase I hypersensitive site is positioned 3' of the triplet repeat in the wild-type allele in both fibroblasts and skeletal muscle cells. In three unrelated individuals with myotonic dystrophy that have large expansions of the triplet repeat, the allele with the triplet repeat expansion exhibited both overall DNase I resistance and inaccessibility of nucleases to the adjacent hypersensitive site. These results indicate that the triplet repeat expansion alters the adjacent chromatin structure, establishing a region of condensed chromatin, and suggests a molecular mechanism for myotonic dystrophy.

Adult↗
PubMed1998

The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure.

Friedreich ataxia (FRDA), an autosomal recessive, neurodegenerative disease is the most common inherited ataxia. The vast majority of patients are homozygous for an abnormal expansion of a polymorphic GAA triplet repeat in the first intron of the X25 gene, which encodes a mitochondrial protein, frataxin. Cellular degeneration in FRDA may be caused by mitochondrial dysfunction, possibly due to abnormal iron accumulation, as observed in yeast cells deficient for a frataxin homologue. Using RNase protection assays, we have shown that patients homozygous for the expansion have a marked deficiency of mature X25 mRNA. The mechanism(s) by which the intronic GAA triplet expansion results in this reduction of X25 mRNA is presently unknown. No evidence was found for abnormal splicing of the expanded intron 1. Using cloned repeat sequences from FRDA patients, we show that the GAA repeat per se interferes with in vitro transcription in a length-dependent manner, with both prokaryotic and eukaryotic enzymes. This interference was most pronounced in the physiological orientation of transcription, when synthesis of the GAA-rich transcript was attempted. These results are consistent with the observed negative correlation between triplet-repeat length and the age at onset of disease. Using in vitro chemical probing strategies, we also show that the GAA triplet repeat adopts an unusual DNA structure, demonstrated by hyperreactivity to osmium tetroxide, hydroxylamine, and diethyl pyrocarbonate. These results raise the possibility that the GAA triplet-repeat expansion may result in an unusual yet stable DNA structure that interferes with transcription, ultimately leading to a cellular deficiency of frataxin.

Antisense Elements (Genetics)↗
PubMed2005

Sporadic SCA8 mutation resembling corticobasal degeneration.

Spinocerebellar ataxia type 8 (SCA8) is caused by the expansion of CTA/CTG triplet repeats on 13q21. Cases can be familial or sporadic. The clinical findings include cerebellar ataxia with upper motor neuron dysfunction, dysphagia, peripheral sensory disturbances, or cognitive and psychiatric impairments, indicating phenotypic variability in SCA8. We report on a patient with rapidly progressive parkinsonism-plus syndrome resembling corticobasal degeneration and triplet expansions in the SCA8 locus. The relationship between clinical phenotype and triplet expansions in the SCA8 locus requires further study.

Aged↗