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Results for “trinucleotide repeat disorders”

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PubMed1996

Huntington's disease.

Huntington's disease (HD) is a late-onset degenerative disorder of the central nervous system, caused by a dominantly inherited mutation in a gene on chromosome 4p. The identification of the trinucleotide repeat mutation responsible for this disorder has been an important step towards understanding the molecular pathology of HD, but in the meantime has also made it possible to offer predictive testing and prenatal diagnosis to individuals at high genetic risk. Predictive testing offers obvious benefits for those who receive a favourable result, but also runs the risk of significant psychological and social problems for the families involved. Uptake of testing to date has been limited. Prenatal testing where the pregnancy is at 25% risk carries the same disadvantages as adult predictive testing, because an unfavourable result would also establish that the at-risk parent is a gene carrier; prenatal exclusion testing offers an alternative method of detecting and terminating at-risk pregnancies without revealing the genetic status of the at-risk parent.

Female↗

PubMed1997

Trinucleotide repeat expansion at the myotonic dystrophy locus reduces expression of DMAHP.

Myotonic dystrophy, or dystrophia myotonica (DM), is an autosomal dominant multisystem disorder caused by the expansion of a CTG trinucleotide repeat in the 3' untranslated region of the DMPK protein kinase gene on chromosome 19q13.3 (refs 1-3). Although the DM mutation was identified more than five years ago, the pathogenic mechanisms underlying this most prevalent form of hereditary adult neuromuscular disease remain elusive. Previous work from our laboratory demonstrated that a DNase l-hypersensitive site located adjacent to the repeats on the wild-type allele is eliminated by repeat expansion, indicating that large CTG-repeat arrays may be associated with a local chromatin environment that represses gene expression. Here we report that the hypersensitive site contains an enhancer element that regulates transcription of the adjacent DMAHP homeobox gene. Analysis of DMAHP expression in the cells of DM patients with loss of the hypersensitive site revealed a two- to fourfold reduction in steady-state DMAHP transcript levels relative to wild-type controls. Allele-specific analysis of DMAHP expression showed that steady-state transcript levels from the expanded allele were greatly reduced in comparison to those from the wild-type allele. Together, these results demonstrate that CTG-repeat expansions can suppress local gene expression and implicate DMAHP in DM pathogenesis.

Animals↗

PubMed2000

Distribution of CAG repeat size in the dentatorubral and pallidoluysian atrophy (DRPLA) gene in a normal population in Taiwan.

Dentatorubral and pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder with expansion of trinucleotide CAG repeats in the coding region of the gene. Expansion of the repeat tract beyond the normal range produces gene products with extended polyglutamine tracts. In this study, we analyzed the distribution of the CAG repeats in the DRPLA alleles in a normal Taiwanese population. We observed 15 different alleles and found that the range of the CAG repeat number was from 7-21. The most frequent allele contained 15 CAG repeats that represented 20% of the total analyzed alleles, followed by the 17 repeats (15.8%). The heterozygosity rate of this locus was 88%. Twelve parents-to-children transmissions of the DRPLA alleles in a Machado-Joseph disease family appeared to be normal without any alteration of the CAG repeat numbers. Phenotypes of DRPLA overlapped those of autosomal dominant cerebellar ataxia (ADCA). In order to identify DRPLA patients in Taiwan, we screened six autosomal dominant cerebellar ataxia patients without expansion in known spinocerebellar ataxia genes. All six patients had the repeat numbers within the normal range; thus, the possibility of DRPLA could be excluded.

Alleles↗

PubMed1993

Anticipation in bipolar affective disorder.

Anticipation refers to the increase in disease severity or decrease in age at onset in succeeding generations. This phenomenon, formerly ascribed to observation biases, correlates with the expansion of trinucleotide repeat sequences (TNRs) in some disorders. If present in bipolar affective disorder (BPAD), anticipation could provide clues to its genetic etiology. We compared age at onset and disease severity between two generations of 34 unilineal families ascertained for a genetic linkage study of BPAD. Life-table analyses showed a significant decrease in survival to first mania or depression from the first to the second generation (P < .001). Intergenerational pairwise comparisons showed both a significantly earlier age at onset (P < .001) and a significantly increased disease severity (P < .001) in the second generation. This difference was significant under each of four data-sampling schemes which excluded probands in the second generation. The second generation experienced onset 8.9-13.5 years earlier and illness 1.8-3.4 times more severe than did the first generation. In additional analyses, drug abuse, deaths of affected individuals prior to interview, decreased fertility, censoring of age at onset, and the cohort effect did not affect our results. We conclude that genetic anticipation occurs in this sample of unilineal BPAD families. These findings may implicate genes with expanding TNRs in the genetic etiology of BPAD.

Adult↗

PubMed1993

Genes with triplet repeats: candidate mediators of neuropsychiatric disorders.

Recently a new form of human mutation-expansion of trinucleotide repeats-has been found to cause the diseases of fragile X syndrome, spinal and bulbar muscular atrophy, myotonic dystrophy and, most recently, Huntington's disease. We review the emerging data on the genetics and neurobiology of these disorders. Three are characterized by unusual patterns of inheritance, in particular, genetic 'anticipation', in which the severity of the disorder increases and the age of onset decreases in successive generations of a pedigree. Several idiopathic neuropsychiatric disorders have features of inheritance consistent with anticipation. In bipolar affective disorder, there is evidence for both earlier age of onset and more severe illness in the second generation of a subset of unilineal pedigrees. There is also the suggestion of anticipation in some forms of schizophrenia, spinocerebellar atrophy and autism. Triplet repeats are present in additional known genes, both in coding regions and untranslated regions. Furthermore, many novel genes with triplet repeats are expressed in the human brain, and these are candidates to cause some forms of these neuropsychiatric disorders.

Humans↗

PubMed1995

Characterization of cDNA clones containing CCA trinucleotide repeats derived from human brain.

Expansion mutation is the cause of eight neuropsychiatric disorders. Thus far each disease is the result of expansion of a C-G rich trinucleotide repeat that is polymorphic for length in the general population. We now report the identification of seven novel cDNA clones with CCA or equivalent trinucleotide repeats obtained by screening a human frontal cortex cDNA library. The repeat lengths of two clones, CCA11 (linked to D20S101, expressed in human brain as a 3.2 kb message) and CCA38 (linked to D5S404), are highly polymorphic in a normal human population. CCA54, mapped to chromosome 19, appears to correspond to a portion of the human gene encoding the alpha 1 subunit of a P-type calcium channel. Expansion mutations at these loci should be considered as possible candidates in evaluating the genetic etiologies of diseases linked to chromosomes 5, 19, and 20.

Base Sequence↗

PubMed1999

Insertion of expanded CAG trinucleotide repeat motifs into a yeast artificial chromosome containing the human Machado-Joseph disease gene.

Machado-Joseph disease or spinocerebellar ataxia 3 (SCA3) is a progressive neurodegenerative disorder caused by pathological expansion of a trinucleotide repeat motif present within exon 4 of the MJD1 gene. Previous attempts to create a transgenic animal model have failed to produce a neurological deficit truly representative of the disease phenotype. This appears to be the result of inappropriate expression of the mutant protein in neuronal populations generally spared in the disease state. Introduction of a human disease gene in the context of a yeast artificial chromosome clone containing endogenous regulatory elements would enhance the potential for correct tissue/cell-specific expression at physiological levels. We report the introduction of expanded CAG repeat motifs into a 250kb yeast artificial chromosome clone spanning the MJD1 locus using two rounds of homologous recombination. Transformants exhibited both expansions and contractions of the motif with alleles ranging in size from 48 to 84 repeat units. The availability of these clones for modelling of the disease in transgenic animals should allow elucidation of the role of repeat length in the phenotypic spectrum of the disease.

Ataxin-3↗

PubMed1995

SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat.

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant inherited disorder characterized by degeneration of cerebellar Purkinje cells, spinocerebellar tracts, and selective brainstem neurons owing to the expansion of an unstable CAG trinucleotide repeat. To gain insight into the pathogenesis of the SCA1 mutation and the intergenerational stability of trinucleotide repeats in mice, we have generated transgenic mice expressing the human SCA1 gene with either a normal or an expanded CAG tract. Both transgenes were stable in parent to offspring transmissions. While all six transgenic lines expressing the unexpanded human SCA1 allele had normal Purkinje cells, transgenic animals from five of six lines with the expanded SCA1 allele developed ataxia and Purkinje cell degeneration. These data indicate that expanded CAG repeats expressed in Purkinje cells are sufficient to produce degeneration and ataxia and demonstrate that a mouse model can be established for neurodegeneration caused by CAG repeat expansions.

Animals↗

PubMed2003

Phenotypic features of Huntington's disease-like 2.

Huntington's disease-like 2 is an autosomal dominantly inherited disorder due to an expansion of trinucleotide repeats. It resembles classic Huntington's disease in clinical phenotype, inheritance pattern, and neuropathological features. We highlight the clinical features of this disorder, including chorea, dystonia, parkinsonism, and cognitive deficits.

Adult↗

PubMed2004

The effect of pre-mutation of X chromosome CGG trinucleotide repeats on brain anatomy.

Expanded trinucleotide repeats are associated with several neuropsychiatric disorders, including fragile X syndrome (FraX) which is the most common inherited form of mental retardation. It is currently thought that FraX results from having >200 CGG trinucleotide repeats, with consequent methylation of the fragile X mental retardation gene (FMR1) and loss of FMR1 protein (FMRP). Pre-mutation carriers of FraX (with 55-200 CGG trinucleotide repeats) were originally considered unaffected, although recent studies challenge this view. However, there are few studies on the effect of pre-mutation trinucleotide repeat expansion on the male human brain using quantitative MRI. Also the results of prior investigations may be confounded because people were selected on the basis of clinical and neurological features, and not genetic phenotype. We compared the brain anatomy of 20 adult male pre-mutation members of known FraX families with 20 healthy male controls. The two groups did not differ significantly in age, intelligence quotient (IQ) or handedness. We also investigated whether any observed effects were associated with: (i) ageing; (ii) expansion of pre-mutation CGG trinucleotide repeats; (iii) reduction in the percentage of lymphocytes staining with anti-FMRP antibodies [%FMRP(+) lymphocytes]; and (iv) elevation of FMR1 mRNA levels. Male pre-mutation carriers of FraX, compared with matched controls, had significantly less voxel density in several brain regions, including the cerebellum, amygdalo-hippocampal complex and thalamus. Within pre-mutation carriers of FraX, ageing, increases in the number of CGG trinucleotide repeats and decreases in %FMRP(+) lymphocytes were associated with decreasing voxel density of regions previously identified as decreased relative to controls. Regional grey and white matter density is significantly affected in male pre-mutation carriers of FraX recruited on the basis of genetic, not clinical, phenotype. The association of voxel density reduction and ageing is consistent with observations of a subgroup of older pre-mutation males who present with cognitive decline. Moreover, our findings suggest, for the first time, an association between voxel density reduction and genetic variation in FraX.

Adolescent↗

PubMed1997

Three CAG trinucleotide repeats on chromosome 6 (D6S1014, D6S1015, and D6S1058) are not expanded in 30 families with schizophrenia.

Since 1991, more than five neuro-genetic disorders have been recognized to be caused by trinucleotide repeat expansions, and the list of such disease should grow. The diseases are characterized clinically by the phenomenon of anticipation, i.e., worsening of the disease phenotype in successive generations with increasing trinucleotide repeat expansion. The presence of anticipation in familial schizophrenia has been suggested. Several studies have provided supportive evidence that the suceptability locus for schizophrenia is on chromosome 6. Therefore, we analyzed three CAG trinucleotide repeat clones D6S1014, D6S1015, and D6S1058 on chromosome 6, which are polymolphic in 30 families with schizophrenia. No unusually, long alleles that would suggest abnormal expansion of more than 35 trinucleotide repeats were observed for these genes. Also, no statistically significant differences were found between the offspring and parental generations of affected subjects or between the affected and unaffected subjects in families with schizophrenia.

Adult↗

PubMed2001

[Experimental therapy: reactivation of the FMR1 gene involved in fragile X syndrome].

Fragile X syndrome represents the most common inherited cause of mental retardation worldwide. Fragile X belongs to a large group of more than 200 mental retardation conditions caused by mutations in X-linked genes (XLMR), that have a collective frequency of up to 1 in 1000 males. Fragile X syndrome is also unique because it was the first genetic condition caused--in the overwhelming majority of cases--by the expansion of an unstable CGG repeat, becoming the prototype of a growing list of inherited disorders due to the instability of trinucleotide repeats. Ten years after the cloning of the FMR1 gene involved in fragile X syndrome, we still don't know all the molecular players that allow the destabilization of the CGG repeat located close to the gene's CpG island. However, the finding of a founder effect in fragile X syndrome indicates that only few of the unstable repeats eventually reached the pathological range. The line of research was aimed at understanding what happens after the fragile X mutation has reached a pathological size. What we showed with our 'reactivation' experiments is that the size of the CGG expansion per se does not cause the silencing of the FMR1 gene: it's the methylation that is added to the expansion that leads to the transcriptional block. Thus, by studying the 'reactivation' of fragile X full mutations, we try to learn more about their 'inactivation' and--hopefully--about possible ways of preventing or 'reverting' their inactivation in fragile X children.

Child↗

PubMed2006

Expression and characterization of full-length human huntingtin, an elongated HEAT repeat protein.

Huntington disease is an inherited neurodegenerative disorder that is caused by expanded CAG trinucleotide repeats, resulting in a polyglutamine stretch of >37 on the N terminus of the protein huntingtin (htt). htt is a large (347 kDa), ubiquitously expressed protein. The precise functions of htt are not clear, but its importance is underscored by the embryonic lethal phenotype in htt knock-out mice. Despite the fact that the htt gene was cloned 13 years ago, little is known about the properties of the full-length protein. Here we report the expression and preliminary characterization of recombinant full-length wild-type human htt. Our results support a model of htt composed entirely of HEAT repeats that stack to form an elongated superhelix.

Animals↗

PubMed1993

[Progress in molecular genetic diagnosis].

The most frequent monogenically inherited disorders and an increasing number of rare monogenic disorders are already mapped, and the genetic defect leading to the disease was in part of the genes identified. Thus, detection of carriers of different disorders becomes possible by indirect or direct genotype analysis. The introduction of new analytical methods, e.g. polymerase chain reaction (PCR) and microsatellites permits a faster and safer diagnosis and in addition, a smaller amount of biological material is necessary. The identification of genes that are mutated in different inherited malignancies improves cancer prevention strategies in these families. A new class of gene defects--the "dynamic" mutations--consisting in the expansion of trinucleotid repeats within disease genes was identified in several disorders (e.g. fragile X-Syndrome, Huntington's disease, myotonic dystrophy); expanding trinucleotid repeats may explain some problems regarding the mode of inheritance and anticipation observed in these disorders, that were so far not understood. For studies of complex genetic disorders several new approaches were developed, however, so far they cannot be used for diagnostic purposes.

DNA Mutational Analysis↗

PubMed1994

Genetic anticipation. Expanding tandem repeats.

The recent discovery that expanding trinucleotide repeats are a form of mutation is a radical departure from the traditional genetic principles of inheritance based on the stable transmission of DNA sequences. The concept that a gene may be altered from tissue to tissue in a single individual or from one generation to the next and that it may confer increasing mutability on itself has provided some insight into the phenomenon of anticipation as manifested by increasing severity, declining age of onset, and increasing penetrance in several inherited disorders. This concept raises the question of how common this mutational mechanism may be in the causes of genetic disease. For example, expansions of trinucleotide repeats may be the underlying mechanism for other disorders that show features suggestive of anticipation such as schizophrenia, bipolar affective disorder, autism and other hereditary ataxias. Expressed genes with trinucleotide repeats have been observed in fetal and adult brains. A recent approach to identifying expanded repeats may simplify the process of finding candidate genes. It is intriguing to speculate how often observations such as intrafamilial variation and even new mutations may be due to such a mechanism. Systematic studies of families with disorders found to be associated with such repeats will be necessary. The implications in genetic counseling for prediction of postnatal outcome as well as risks of recurrence are truly staggering. Meanwhile, the immediate benefit of the knowledge of trinucleotide repeat expansions concerning the six disorders discussed will be the application of direct methods of diagnosis avoiding linkage analysis. The long-term benefits may very well be the discovery of more effective treatment modalities based on correction of the gene defects. Exciting times for human genetics appear to be at hand.

Cerebellar Ataxia↗

PubMed2000

Mini- and microsatellite expansions: the recombination connection.

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.

Animals↗

PubMedDate not supplied

[Clinical and genetic implications of dynamic mutations in neuropediatric practice].

Dynamic mutations are a new type of genetic alteration identified in recent years. They are due to an increased number of repetitions of a particular trinucleotide and are associated with a particular group of neurological and/or neuromuscular disorders. They are characterized by intergenerational and intragenerational instability. There is an inversely proportional relationship between the number of repetitions and the age at which the first symptoms are seen (genetic anticipation). To date 13 disorders, due to this type of mutation, have been described. Some, such as sex-linked mental retardation (fragile X), myotonic dystrophy or Friedreich's ataxia involve an anomalous number of repetitions, reaching over a thousand of a given trinucleotide. Another group known as the polyglutamine disorders, since the CAG trinucleotide is repeated in all cases (dominant and familial ataxias, Huntington's disease) have an increased number of repetitions but there are less than a hundred of them. Finally, recently a third group has been described, oculo-pharyngeal dystrophy with less than a dozen repetitions. Why an increased number of repetitions of a trinucleotide found in or out of a gene is associated with a particular disorder is one of the questions raised by these mutations and which is starting to be discovered.

Child↗

PubMed1999

Structural properties of Friedreich's ataxia d(GAA) repeats.

The expansion of trinucleotide repeat sequences is the underlying cause of a growing number of inherited human disorders. To provide correlations between DNA structure and mechanisms of trinucleotide repeat expansion, we investigated potential secondary structures formed from the complementary strands of d(GAA.TTC)n, a sequence whose expansion is associated with Friedreich's ataxia. In 50 mM NaCl, pH 7.5, d(GAA)15 exhibited a cooperative and reversible decrease in large circular dichroism bands at 248 and 272-274 nm over the temperature range of 5-50 degrees C, providing evidence for a base-paired structure at reduced temperatures. Ultraviolet absorbance melting profiles indicated that the melting temperature (Tm) of d(GAA)15 was 40 degrees C. At 5 degrees C, the central portion of d(GAA)15 was hypersensitive to single-strand-specific P1 nuclease degradation and diethyl pyrocarbonate modification, providing evidence for a hairpin conformation. At temperatures between 25 and 35 degrees C in 50 mM NaCl, the triplet repeat region of d(GAA)15 was uniformly resistant to degradation by P1 nuclease, including the central portion of the sequence. Our results indicate that the structure of d(GAA)15 is a hairpin at 5 degrees C, unknown but partially base-paired at 37 degrees C, and an approximately random coil above 65 degrees C.

Circular Dichroism↗