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At least 19 recordsLinked to original sources
PubMed1994

Trinucleotide repeat expansion in neurological disease.

Expansion of trinucleotide repeats is now recognized as a major cause of neurological disease. At least seven disorders result from trinucleotide repeat expansion: X-linked spinal and bulbar muscular atrophy (SBMA), two fragile X syndromes of mental retardation (FRAXA and FRAXE), myotonic dystrophy, Huntington's disease, spinocerebellar ataxia type 1 (SCA1), and dentatorubral-pallidoluysian atrophy (DRPLA). The expanded trinucleotide repeats are unstable, and the phenomenon of anticipation, i.e., worsening of disease phenotype over successive generations, correlates with increasing expansion size. In this review, we compare the clinical and molecular features of the trinucleotide repeat diseases, which may be classified into two types. Fragile X and myotonic dystrophy are multisystem disorders usually associated with large expansions of untranslated repeats, while the four neurodegenerative disorders, SBMA, Huntington's disease, SCA1, and DRPLA, are caused by smaller expansions of CAG repeats within the protein coding portion of the gene. CAG repeats encode polyglutamine tracts. Polyglutamine tract expansion thus appears to be a common mechanism of inherited neurodegenerative disease. Although polyglutamine tract lengthening presumably has a toxic gain of function effect in the CAG trinucleotide repeat disorders, the basis of this neuronal toxicity remains unknown.

Humans↗
PubMed1995

Trinucleotide repeat expansion and human disease.

Trinucleotide repeat expansions have been identified as the underlying mutation in an increasing number of human genetic diseases, such as fragile site syndromes, myotonic dystrophy and several neurodegenerative disorders including Huntington's disease. By an unknown mechanism, polymorphic GC-rich triplet repeats expand in all these diseases. The expansions of a CCG repeat in fragile-site-associated disorders and the CTG repeat (in the 3'-untranslated region of the myotonin kinase gene) causing myotonic dystrophy are very large, whereas small expansions of CAG repeats have been identified in the open reading frame of genes in a number of neurological genetic disorders.

Age of Onset↗
PubMed1994

Trinucleotide repeat expansions and human genetic disease.

Trinucleotide repeat expansions are now a well-established mutational mechanism in human genetic disease. An unstable CAG repeat is known to be responsible for three neurodegenerative disorders: Huntington's disease, spinal and bulbar muscular atrophy and spinocerebellar ataxia type 1. Similarities in the genetics of these diseases, the size of the repeat expansions and the position of the unstable repeat within the gene (when known) suggest a common basis to the observed phenotypes. The cloning of two regions at which chromosome breakage can be induced (FRAXA and FRAXE) has in each case uncovered an unstable CG-rich triplet repeat which becomes methylated when fully expanded. In addition to these two classes of mutation, the presence of an expanded CTG repeat in the 3' untranslated region of a protein kinase causes myotonic dystrophy. The size of the respective expansions, repeat stability, mutational origins and possible mechanisms of action are discussed.

Adult↗
PubMed1995

Translational suppression by trinucleotide repeat expansion at FMR1.

Fragile X syndrome is the result of the unstable expansion of a trinucleotide repeat in the 5'-untranslated region of the FMR1 gene. Fibroblast subclones from a mildly affected patient, each containing stable FMR1 alleles with 57 to 285 CGG repeats, were shown to exhibit normal steady-state levels of FMR1 messenger RNA. However, FMR protein was markedly diminished from transcript with more than 200 repeats. Such transcripts were associated with stalled 40S ribosomal subunits. These results suggest that a structural RNA transition beyond 200 repeats impedes the linear 40S migration along the 5'-untranslated region. This results in translational inhibition by trinucleotide repeat expansion.

Centrifugation, Density Gradient↗
PubMed1993

Trinucleotide repeat expansions in neurological disease.

During the past year, new examples of human neurological disease have been discovered that have an unprecedented type of mutation as their cause: the remarkable expansion of trinucleotide repeats. These triplet repeats are normally polymorphic and exonic, though not always coding. In disease states they become markedly unstable and may expand moderately or by thousands of repeats in a single generation, influencing gene expression, message stability or protein structure.

Fragile X Syndrome↗
PubMed2022

Suppression of trinucleotide repeat expansion in spermatogenic cells in Huntington's disease.

Trinucleotide repeats (TNRs) are dispersed throughout the human genome. About 20 loci are related to human diseases, such as Huntington's disease (HD). A larger TNR instability is predominantly observed in the paternal germ cells in some TNR disorders. Suppressing the expansion during spermatogenesis can provide a unique opportunity to end the vicious cycle of genetic anticipation. Here, using an in vitro differentiation method to derive advanced spermatogenic cells, we investigated the efficacy of two therapeutic agents, araC (cytarabine) and aspirin, on stabilizing TNRs in spermatogenic cells. Two WT patient-derived induced pluripotent stem cell (iPSC) lines and two HD hiPSC lines, with 44 Q and 180 Q, were differentiated into spermatogonial stem cell-like cells (SSCLCs). Both HD cell lines showed CAG tract expansion in SSCLC. When treated with araC and aspirin, HD1 showed moderate but not statistically significant stabilization of TNR. In HD2, 10 nM of aspirin and araC showed significant stabilization of TNR. All cell lines showed increased DNA damage response (DDR) gene expression in SSCLCs while more genes were significantly induced in HD SSCLC. In HD1, araC and aspirin treatment showed general suppression of DNA damage response genes. In HD2, only FAN1, OGG1, and PCNA showed significant suppression. When the methylation profile of HD cells was analyzed, FAN1 and OGG1 showed significant hypermethylation after the aspirin and araC treatment in SSCLC compared to the control. This study underscores the utility of our in vitro spermatogenesis model to study and develop therapies for TNR disorders such as HD.

Male↗
PubMed1996

[Analysis of trinucleotide repeat expansion as a new mechanism of mutation in Huntington's chorea: theoretical and applied aspects].

The Huntington's chorea mutation consists of expansion of trinucleotide CAG repeats in the recently discovered gene IT-15. In this work, for the first time in a population of Russian patients, correlations between the number of copies of CAG repeats and various clinical characteristics of the disease are investigated. It is established that the degree of triplet expansion determines the age of onset of the disease and the rate of progression of the neurological and mental symptoms of Huntington's chorea, and it is also shown that the genetic instability of the mutant allele is considerably higher upon transmission of the disease gene along the paternal line. We obtained direct confirmation of the possibility of genetic instability of a normal allele inherited paternally. In this work, the first successful direct (including preclinical) DNA diagnosis in Russia of Huntington's chorea was obtained.

Age of Onset↗
PubMed1994

Myotonic dystrophy with no trinucleotide repeat expansion.

We report 3 patients from 2 families with myotonic dystrophy who do not show an abnormal expansion of CTG trinucleotide repeats within the myotonic dystrophy gene. Characteristic features of myotonic dystrophy in these patients were frontal balding, cataracts, cardiac conduction abnormalities, and testicular atrophy with myotonia and muscle weakness. Results of muscle histopathology were consistent with myotonic dystrophy. Genetic analysis of leukocyte and muscle DNA showed a normal number of CTG repeats. The demonstration of normal CTG repeat number for the myotonic dystrophy gene does not exclude the diagnosis of myotonic dystrophy.

Adult↗
PubMed1996

A reproducible assay of polymerase chain reaction to detect trinucleotide repeat expansion of Huntington's disease and senile chorea.

A simple and reproducible method of polymerase chain reaction (PCR) assay was established to detect trinucleotide repeat expansion for Huntington's disease (HD) using a new DNA polymerase and buffer system. The system consists of an extremely heat stable DNA polymerase (Pfu), and a buffer supplemented with ammonium sulfate and dimethyl sulfoxide. Previous methods to amplify expanded alleles for HD have been very complex in PCR conditions, but the reproducibility was sometimes very low because of repetitive sequences around the primer sequences. With the present method, strong bands for the disease alleles were reproducibly visible in a conventional agarose gel stained with ethidium bromide without using isotopes. Three cases with sporadic HD and a case with senile chorea showed expanded alleles for HD with smaller sizes of the expansion than cases with typical HD. These results showed that the present method provides a simple and reproducible way to detect HD allele, and some cases with sporadic HD and senile chorea had expanded HD alleles.

Adult↗
PubMed1995

Screening for CGG trinucleotide repeat expansion in the fragile X mental retardation 1 gene in schizophrenic patients.

Patients diagnosed using DSM-III-R criteria as having schizophrenia and other related disorders (n = 128) were assessed for CGG trinucleotide repeat expansion in the fragile X mental retardation 1 (FMR-1) gene. One subject, a woman with schizophreniform disorder, was found to have a premutation of the gene. Her case report is given. The present investigation supports the view that mutation or premutation of the FMR-1 gene is not of importance for the aetiology of the vast majority of schizophrenic patients.

Adult↗
PubMed1995

Spinal and bulbar muscular atrophy: a trinucleotide-repeat expansion neurodegenerative disease.

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.

Humans↗
PubMed1992

Human genes containing polymorphic trinucleotide repeats.

Expansions of trinucleotide repeats within gene transcripts are responsible for fragile X syndrome, myotonic dystrophy and spinal and bulbar muscular atrophy. To identify other human genes with similar features as candidates for triplet repeat expansion mutations, we screened human cDNA libraries with repeat probes and searched databases for transcribed genes with repeats. From both strategies, 40 genes were identified and 14 characterized. Five were found to contain repeats which are highly polymorphic including the N-cadherin, BCR, glutathione-S-transferase and Na+/K+ ATPase (beta-subunit) genes. These data demonstrate the occurrence of other human loci which may undergo this novel mechanism of mutagenesis giving rise to genetic disease.

Base Sequence↗
PubMed1994

Improving diagnosis of Huntington's disease by analysis of an intragenic trinucleotide repeat expansion.

OBJECTIVE: To develop an accurate presymptomatic test for Huntington's disease. METHOD: An improved polymerase chain reaction method was used to investigate the pattern of expansions of a CAG repeat sequence located in the 5' region of a gene recently found to produce the protein called Huntingtin. We documented the range of trinucleotide repeat expansions in the responsible gene in 82 affected individuals compared with 80 control subjects from a Western Australian population. RESULTS: The number of expanded repeats ranged from 40 to 73 in affected individuals and from 13 to 38 in normal controls. CONCLUSIONS: Polymerase chain reaction analysis of a CAG repeat sequence in the Huntington's disease gene clearly differentiated between normal and mutated alleles, providing an accurate diagnostic test for the disorder in individuals at risk. This predictive test has met with greater acceptance and demand than methods using family based linkage studies.

Base Sequence↗
PubMed1994

The cloning of FRAXF: trinucleotide repeat expansion and methylation at a third fragile site in distal Xqter.

Three fragile sites, FRAXA, FRAXE and FRAXF lie in the Xq27-28 region of the human X chromosome. The expression of FRAXA is associated with the fragile X syndrome, the most prevalent form of inherited mental retardation whilst the expression of FRAXE is associated with a rarer and comparatively milder form of mental handicap. Both the FRAXA and FRAXE sites have been cloned and the fragile site expression found to be due to the expansion of analogous CGG/GCC trinucleotide repeat arrays. We describe here the cloning of the third fragile site, FRAXF, and demonstrate that it involves the expansion of a (GCCGTC)n(GCC)n compound array. PCR analyses across the repeat of normal individuals show that the number of triplets in the array ranges from 12-26 and the most common allele consists of 14 triplet units. Sequencing analyses show that 95% of normal individuals have three copies of the GCCGTC motif and in these individuals, the size variation observed by PCR is due to copy number alterations in the GCC array. In a cytogenetically positive male with developmental delay, the array is expanded by > 900 triplets and the adjacent CpG-rich region is methylated. The array is also expanded in cytogenetically positive carrier females from the family originally used to define the FRAXF site. We conclude that the expanded array corresponds to the FRAXF fragile site.

Base Sequence↗
PubMed1994

The trinucleotide repeat expansion on chromosome 6p (SCA1) in autosomal dominant cerebellar ataxias.

Affected members of 73 families with a variety of autosomal dominant late onset cerebellar ataxias (ADCAs) were investigated for the trinucleotide (CAG) repeat expansion which is found in pedigrees exhibiting linkage to the SCA1 locus on chromosome 6. Most of the families were too small for linkage analysis. The mutation was only found in ADCA type I, in 19 out of 38 such kindreds investigated (50%). It was slightly more common in Italian (59%) than British (50%) families, and was also found in Malaysian, Bangladeshi and Jamaican kindreds. Overall, ADCA type I patients with the expansion had a lower incidence of hyporeflexia and facial fasciculation than those without. The trinucleotide expansion was not found in eight families with ADCA and maculopathy or 24 kindreds with a pure type of ADCA, confirming that these syndromes are genetically distinct. It was also not detected in 12 patients with sporadic degenerative ataxias. DNA analysis for the SCA1 mutation is useful diagnostically in single patients or small families, and can be used for presymptomatic testing where appropriate.

Adolescent↗
PubMed1995

Detection of the Machado-Joseph disease/spinocerebellar ataxia three trinucleotide repeat expansion in families with autosomal dominant motor disorders, including the Drew family of Walworth.

Affected members of 63 families with a variety of autosomal dominant late onset cerebellar ataxias (ADCA), and 29 patients with similar phenotypes but no affected relatives, were investigated for the trinucleotide (CAG) repeat expansion described in Japanese families with Machado-Joseph disease (MJD). This disorder had previously been shown to map to the region of chromosome 14 which also contains a locus causing ADCA in French families, spinocerebellar ataxia 3 (SCA3). The MJD/SCA3 mutation was identified in nine families with ADCA type I, and a further family in which affected members had parkinsonism, peripheral neuropathy, dystonia, and spasticity, but little evidence of cerebellar disease. Only one of the 10 families was British (the Drew family of Walworth); the others originated from India, Jamaica, Ghana, Brazil and France. There was no single clinical feature which distinguished patients with the MJD/SCA3 mutation from those with the CAG expansion on chromosome 6 (SCA1) or ADCA type I families with no known mutation. The CAG repeat length ranged from 13-41 copies on normal chromosomes and 62-80 copies on affected chromosomes. There was a significant inverse correlation between age of onset of symptoms and repeat length, but no significant effect of parental sex on repeat length or age of onset in offspring. DNA analysis for the MJD/SCA3 mutation is useful for diagnosis in patients with familial ataxic or extrapyramidal syndromes, and will aid genetic counselling in these disorders.

Adolescent↗
PubMed1994

Analysis of the trinucleotide repeat expansion in Italian families affected with Huntington disease.

150 subjects affected with HD and 45 at high risk for the disease were typed for the CAG trinucleotide repeat at the 5' end of IT15. In all of them we find expanded segments showing marked instability upon transmission. Their length distribution matches those previously reported and inversely correlates (-0.686) with age at onset. Two at risk sibs from a large HD pedigree show expanded segments that overlap the normal distribution and can represent reductions from the HD to the normal range. A case of instability on a normal chromosome is also reported. Finally, an analysis of the CAG repeat as a function of three polymorphic DNA markers at D4S127 and D4S95 loci shows no significant difference in the average repeat length on HD chromosomes grouped according to the cosegregating allele of each marker or to the corresponding haplotype. Despite the marked heterogeneity in repeat length among HD families, haplotypes are not associated with different values around which the repeat length fluctuates.

Age of Onset↗