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Brain Research Aug 2018Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset inherited neurodegenerative disorder characterized by progressive intention tremor, gait ataxia and... (Review)
Review
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset inherited neurodegenerative disorder characterized by progressive intention tremor, gait ataxia and dementia associated with mild brain atrophy. The cause of FXTAS is a premutation expansion, of 55 to 200 CGG repeats localized within the 5'UTR of FMR1. These repeats are transcribed in the sense and antisense directions into mutants RNAs, which have increased expression in FXTAS. Furthermore, CGG sense and CCG antisense expanded repeats are translated into novel proteins despite their localization in putatively non-coding regions of the transcript. Here we focus on two proposed disease mechanisms for FXTAS: 1) RNA gain-of-function, whereby the mutant RNAs bind specific proteins and preclude their normal functions, and 2) repeat-associated non-AUG (RAN) translation, whereby translation through the CGG or CCG repeats leads to the production of toxic homopolypeptides, which in turn interfere with a variety of cellular functions. Here, we analyze the data generated to date on both of these potential molecular mechanisms and lay out a path forward for determining which factors drive FXTAS pathogenicity.
Topics: 5' Untranslated Regions; Ataxia; Fragile X Mental Retardation Protein; Fragile X Syndrome; Gene Expression Regulation; Humans; Mutation; Neurodegenerative Diseases; Tremor; Trinucleotide Repeat Expansion; Trinucleotide Repeats
PubMed: 29453961
DOI: 10.1016/j.brainres.2018.02.006 -
EMBO Reports Aug 2000It is widely accepted that the large trinucleotide repeat expansions observed in many neurological diseases occur during replication. However, genetic recombination has... (Review)
Review
It is widely accepted that the large trinucleotide repeat expansions observed in many neurological diseases occur during replication. However, genetic recombination has emerged as a major source of instability for tandem repeats, including minisatellites, and recent studies raise the possibility that it may also be responsible for trinucleotide repeat expansions. We will review data connecting tandem repeat rearrangements and recombination in humans and in eukaryotic model organisms, and discuss the possible role of recombination in trinucleotide repeat expansions in human neurological disorders.
Topics: Animals; DNA; DNA Repair; Gene Conversion; Humans; Meiosis; Minisatellite Repeats; Models, Genetic; Recombination, Genetic; Tandem Repeat Sequences; Trinucleotide Repeat Expansion
PubMed: 11265750
DOI: 10.1093/embo-reports/kvd031 -
Nucleic Acids Research Jun 1997Triplet repeat expansion diseases (TREDs) are characterized by the coincidence of disease manifestation with amplification of d(CAG. CTG), d(CGG.CCG) or d(GAA.TTC)... (Review)
Review
Triplet repeat expansion diseases (TREDs) are characterized by the coincidence of disease manifestation with amplification of d(CAG. CTG), d(CGG.CCG) or d(GAA.TTC) repeats contained within specific genes. Amplification of triplet repeats continues in offspring of affected individuals, which generally results in progressive severity of the disease and/or an earlier age of onset, phenomena clinically referred to as 'anticipation'. Recent biophysical and biochemical studies reveal that five of the six [d(CGG)n, d(CCG)n, (CAG)n, d(CTG)n and d(GAA)n] complementary sequences that are associated with human disease form stable hairpin structures. Although the triplet repeat sequences d(GAC)n and d(GTC)n also form hairpins, repeats of the double-stranded forms of these sequences are conspicuously absent from DNA sequence databases and are not anticipated to be associated with human disease. With the exception of d(GAG)n and d(GTG)n, the remaining triplet repeat sequences are unlikely to form hairpin structures at physiological salt and temperature. The details of hairpin structures containing trinucleotide repeats are summarized and discussed with respect to potential mechanisms of triplet repeat expansion and d(CGG.CCG) n methylation/demethylation.
Topics: Base Sequence; DNA; Genetic Diseases, Inborn; Humans; Models, Molecular; Nucleic Acid Conformation; Trinucleotide Repeats
PubMed: 9171073
DOI: 10.1093/nar/25.12.2245 -
International Journal of Molecular... Jan 2020Myotonic dystrophy type 1 (DM1) is a complex neuromuscular disease caused by an unstable cardiotocography (CTG) repeat expansion in the gene. This disease is... (Review)
Review
Myotonic dystrophy type 1 (DM1) is a complex neuromuscular disease caused by an unstable cardiotocography (CTG) repeat expansion in the gene. This disease is characterized by high clinical and genetic variability, leading to some difficulties in the diagnosis and prognosis of DM1. Better understanding the origin of this variability is important for developing new challenging therapies and, in particular, for progressing on the path of personalized treatments. Here, we reviewed CTG triplet repeat instability and its modifiers as an important source of phenotypic variability in patients with DM1.
Topics: Animals; Biological Variation, Population; Cardiotocography; Humans; Myotonic Dystrophy; Myotonin-Protein Kinase; Phenotype; Trinucleotide Repeats
PubMed: 31936870
DOI: 10.3390/ijms21020457 -
Trends in Neurosciences Oct 1995Spinal and bulbar muscular atrophy (SBMA) is an X-linked, adult-onset motor neuronopathy that is caused by expansion of a trinucleotide (CAG) repeat in the... (Review)
Review
Spinal and bulbar muscular atrophy (SBMA) is an X-linked, adult-onset motor neuronopathy that is caused by expansion of a trinucleotide (CAG) repeat in the androgen-receptor gene. The length of this repeat varies as it is passed down through SBMA families, and correlates inversely with the age of onset of the disease. The motor-neuron degeneration that occurs in this disease is probably caused by a toxic gain of function in the androgen-receptor protein. Subsequent to the identification of the mutation in SBMA, other inherited neurodegenerative diseases have been found to be caused by the expansion of CAG repeats in the coding regions of other genes. Because these diseases probably share a common pathogenesis, investigation of SBMA might help to determine a general mechanism of neuronal degeneration.
Topics: Humans; Muscular Atrophy, Spinal; Nerve Degeneration; Receptors, Androgen; Trinucleotide Repeats
PubMed: 8545913
DOI: 10.1016/0166-2236(95)94497-s -
Nutricion Hospitalaria Dec 2015the human androgen receptor (AR) gene possesses two trinucleotide polymorphic repeats, (CAG and GGN) that affect the amount of AR protein translated. In this study, we...
INTRODUCTION
the human androgen receptor (AR) gene possesses two trinucleotide polymorphic repeats, (CAG and GGN) that affect the amount of AR protein translated. In this study, we genotyped these polymorphic tracts in a representative sample of Caucasian children (Tanner ≤ 5), 152 boys (11.5 } 2.6 yrs) and 116 girls (10.1 } 3.2 yrs) from Spain and investigated their association with bone mass.
METHODS
the length of CAG and GGN repeats was determined by PCR and fragment analysis. Body composition was assessed by dual energy x-ray absorptiometry (DXA). Individuals were grouped as CAG short (CAGS) if harboring repeat lengths of ≤ 21 and CAG long (CAGL) if CAG > 21. Moreover, subjects were grouped as GGN short (GGNS) if harboring repeat lengths of ≤ 23 and GGN long (GGNL) if GGN > 23.
RESULTS
in boys, significant differences in height, body mass, whole body bone mineral density (BMD) and content (BMC), upper extremities BMC, lower extremities BMC, femoral neck BMD, Ward's triangle BMC and BMD and lumbar spine BMD were observed between CAGS and CAGL groups (P < 0.05). Thus, upper extremities BMD differed between GGNS and GGNL groups. After adjusting for confounding variables, only upper extremities BMD between GGNS and GGNL groups remained significant (P < 0.05). No differences were observed in girls in any measured site in relation to either CAG or GGN polymorphisms length.
CONCLUSIONS
our results support the hypothesis that longer alleles of the AR CAG and GGN polymorphisms are associated with increased bone mass in prepubertal boys.
Topics: Absorptiometry, Photon; Adolescent; Body Composition; Bone Density; Bone and Bones; Child; Female; Humans; Male; Polymorphism, Genetic; Receptors, Androgen; Sex Characteristics; Trinucleotide Repeats
PubMed: 26667715
DOI: 10.3305/nh.2015.32.6.9767 -
Cell Research Apr 2013Trinucleotide repeat expansions cause 17 heritable human neurological disorders. In some diseases, somatic expansions occur in non-proliferating tissues such as brain...
Trinucleotide repeat expansions cause 17 heritable human neurological disorders. In some diseases, somatic expansions occur in non-proliferating tissues such as brain where DNA replication is limited. This finding stimulated significant interest in replication-independent expansion mechanisms. Aberrant DNA repair is a likely source, based in part on mouse studies showing that somatic expansions are provoked by the DNA repair protein MutSβ (Msh2-Msh3 complex). Biochemical studies to date used cell-free extracts or purified DNA repair proteins to yield partial reactions at triplet repeats. The findings included expansions on one strand but not the other, or processing of DNA hairpin structures thought to be important intermediates in the expansion process. However, it has been difficult to recapitulate complete expansions in vitro, and the biochemical role of MutSβ remains controversial. Here, we use a novel in vitro assay to show that human cell-free extracts catalyze expansions and contractions of trinucleotide repeats without the requirement for DNA replication. The extract promotes a size range of expansions that is similar to certain diseases, and triplet repeat length and sequence govern expansions in vitro as in vivo. MutSβ stimulates expansions in the extract, consistent with aberrant repair of endogenous DNA damage as a source of expansions. Overall, this biochemical system retains the key characteristics of somatic expansions in humans and mice, suggesting that this important mutagenic process can be restored in the test tube.
Topics: Animals; Cell-Free System; DNA Repair; HeLa Cells; Humans; Mice; Models, Biological; MutS DNA Mismatch-Binding Protein; Mutation; Plasmids; Trinucleotide Repeat Expansion
PubMed: 23337586
DOI: 10.1038/cr.2013.12 -
Biomolecular Concepts Mar 2022Polyglutamine (polyQ) diseases are a family composed of nine neurodegenerative inherited disorders (NDDs) caused by pathological expansions of cytosine-adenine-guanine... (Review)
Review
Polyglutamine (polyQ) diseases are a family composed of nine neurodegenerative inherited disorders (NDDs) caused by pathological expansions of cytosine-adenine-guanine (CAG) trinucleotide repeats which encode a polyQ tract in the corresponding proteins. CAG polyQ repeat expansions produce neurodegeneration via multiple downstream mechanisms; among those the neuronal activity underlying the ion channels is affected directly by specific channelopathies or indirectly by secondary dysregulation. In both cases, the altered excitability underlies to gain- or loss-of-function pathological effects. Here we summarize the repertoire of ion channels in polyQ NDDs emphasizing the biophysical features of neuronal excitability and their pathogenic role. The aim of this review is to point out the value of a deeper understanding of those functional mechanisms and processes as crucial elements for the designing and targeting of novel therapeutic avenues.
Topics: Humans; Ion Channels; Neurodegenerative Diseases; Peptides; Trinucleotide Repeats
PubMed: 35357797
DOI: 10.1515/bmc-2022-0018 -
Proceedings of the Japan Academy.... 2022The instability of repeat sequences in the human genome results in the onset of many neurological diseases if the repeats expand above a certain threshold. The...
The instability of repeat sequences in the human genome results in the onset of many neurological diseases if the repeats expand above a certain threshold. The transcripts containing long repeats sequester RNA binding proteins. The mechanism of repeat instability involves metastable slip-out hairpin DNA structures. Synthetic organic chemists have focused on the development of small organic molecules targeting repeat DNA and RNA sequences to treat neurological diseases with repeat-binding molecules. Our laboratory has studied a series of small molecules binding to mismatched base pairs and found molecules capable of binding CAG repeat DNA, which causes Huntington's disease upon expansion, CUG repeat RNA, a typical toxic RNA causing myotonic dystrophy type 1, and UGGAA repeat RNA causing spinocerebellar ataxia type 31. These molecules exhibited significant beneficial effects on disease models in vivo, suggesting the possibilities for small molecules as drugs for treating these neurological diseases.
Topics: DNA; Humans; Myotonic Dystrophy; Nervous System Diseases; RNA; Spinocerebellar Ataxias; Trinucleotide Repeat Expansion
PubMed: 35013029
DOI: 10.2183/pjab.98.003 -
Philosophical Transactions of the Royal... Jun 1999Microsatellites are stretches of repetitive DNA, where individual repeat units comprise one to six bases. These sequences are often highly polymorphic with respect to... (Review)
Review
Microsatellites are stretches of repetitive DNA, where individual repeat units comprise one to six bases. These sequences are often highly polymorphic with respect to repeat number and include trinucleotide repeats, which are abnormally expanded in a number of diseases. It has been widely assumed that microsatellite loci are as likely to gain and lose repeats when they mutate. In this review, we present population genetic and empirical data arguing that microsatellites, including normal alleles at trinucleotide-repeat disease loci, are more likely to expand in length when they mutate. In addition, our experiments suggest that the rates of expansion of such sequences differ in related species.
Topics: Animals; Evolution, Molecular; Genetic Variation; Humans; Huntington Disease; Microsatellite Repeats; Mutation; Trinucleotide Repeat Expansion; Trinucleotide Repeats
PubMed: 10434312
DOI: 10.1098/rstb.1999.0465