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PubMed2006

A multistep mutation mechanism drives the evolution of the CAG repeat at MJD/SCA3 locus.

Despite the intense debate around the repeat instability reported on the large group of neurological disorders caused by trinucleotide repeat expansions, little is known about the mutation process underlying alleles in the normal range that, ultimately, expand to pathological size. In this study, we assessed the mutation mechanisms by which wild-type Machado-Joseph disease (MJD) alleles have been generated throughout human evolution. Haplotypes including the CAG repeat, six intragenic SNPs and four flanking microsatellites were analysed in 431 normal chromosomes of European, Asian and African origin. A bimodal CAG repeat length frequency distribution was found in the four most frequent wild-type lineages (H1-GCGGCA; H2-GTGGCA; H3-TTAGAC and H4-TTACAC). Based on flanking microsatellite haplotypes, the variance calculated by analysis of molecular variance between modal (CAG)n alleles was little or null in lineages H1, H2 and H4, as were the pairwise differences. Moreover, genetic distances among all the alleles from each lineage did not reflect the allele sizes differences, as expected if a stepwise mutation model was the main process of evolution. On the contrary, when exposed in maximum parsimonious phylogenetic trees, a large number of mutation steps separated same-size alleles, whereas several microsatellite haplotypes were shared by modal CAGs. In conclusion, our results suggest that the main mutation mechanism occurring in the evolution of the polymorphic CAG region at MJD/SCA3 locus is a multistep one, either by gene conversion or DNA slippage; repeats with 14, 21, 23 and 27 CAGs are the main alleles involved in this process.

Alleles↗

PubMed2000

Cell death in polyglutamine diseases.

An increasing number of inherited neurodegenerative diseases are known to be caused by trinucleotide repeat expansions in the respective genes. At least nine disorders result from a CAG trinucleotide repeat expansion which is translated into a polyglutamine stretch in the respective proteins: Huntington's disease (HD), dentatorubral pallidolysian atrophy (DRPLA), spinal bulbar muscular atrophy (SBMA), and several of the spinocerebellar ataxias (SCA1, 2, 3, 6, 7 and 12). Although the molecular steps leading to the specific neuropathology of each disease are unknown and are still under intensive investigation, there is increasing evidence that some CAG repeat disorders involve the induction of apoptotic mechanisms. This review summarizes the clinical and genetic features of each CAG repeat disorder and focuses on the common mechanistic steps involved in the disease progression of these so-called polyglutamine diseases. Among the common molecular features the formation of intranuclear inclusions, the recruitment of interacting polyglutamine-containing proteins, the involvement of the proteasome and molecular chaperones, and the activation of caspases are discussed with regard to their potential implication for the induction of cell death.

Animals↗

PubMed2001

Investigation of the CACNA1A gene as a candidate for typical migraine susceptibility.

Typical migraine is a complex neurological disorder comprised of two main subtypes: migraine with (MA) and without aura (MO). The disease etiology is still unclear, but family studies provide strong evidence that defective genes play an important role. Familial hemiplegic migraine (FHM) is a very rare and severe subtype of MA. It has been proposed that FHM and MA may have a similar genetic etiology. Therefore, genetic studies on FHM provide a useful model for investigating the more prevalent types of typical migraine. FHM in some families has been shown to be caused by mutations in a brain-specific P/Q-type calcium channel alpha1 subunit gene (CACNA1A) on chromosome 19p13. There has also been a report of a CACNA1A mutation being associated with MA in a patient from a family with predominant FHM. We have previously demonstrated suggestive linkage of typical migraine in a large Australian family to the FHM region on chromosome 19p13. These findings suggest that CACNA1A may also be implicated in the etiology of typical migraine in this pedigree. To investigate this possibility, we sequenced two patients carrying the critical susceptibility haplotype surrounding CACNA1A. No disease-causing mutations or polymorphisms were revealed in any of the 47 exons screened. To determine whether the CACNA1A gene was implicated in typical migraine susceptibility in the general Caucasian population, we also analyzed 82 independent pedigrees and a large case control group. We did not detect any linkage or association in these groups and conclude that if CACNA1A plays a role in typical migraine, it does not confer a major effect on the disease.

Alleles↗

PubMed1995

Diagnosis of inherited metabolic disorders affecting the nervous system.

Knowledge of the molecular causes for genetic diseases that affect the nervous system is rapidly expanding. Especially striking has been the finding in several autosomal dominant neurodegenerative disorders that unstable expansions of trinucleotide repeats are responsible for the genetic disorder and that the length of the repeat can be correlated with the age of onset and the severity of symptoms. Phenotypic heterogeneity in many disorders associated with enzyme deficiencies can often be linked to the amount of residual enzyme activity occurring with different gene mutations. Making a specific diagnosis of a neurological disorder associated with genetically determined metabolic defects requires access to a laboratory that can assist in arranging for appropriate testing to be carried out. In some disorders such as the aminoacidurias diagnostic metabolic studies can be performed in hospital clinical chemistry laboratories. In others, such as the lysosomal storage diseases, a laboratory that carries out special lipid analyses and white blood cell enzyme assays will be necessary. DNA mutational analyses are becoming commercially available for diagnosing many disorders such as mitochondrial diseases and those conditions associated with expanded trinucleotide repeats. It may be necessary to contact individual research laboratories when confronted with a disorder that has been newly discovered or that is very rare. A computerised directory of specialised laboratories that perform disease specific testing for genetic disorders should be useful in choosing the appropriate diagnostic or research laboratory.

Humans↗

PubMed1999

Eleven trinucleotide repeat loci that map to chromosome 12 excluded from involvement in the pathogenesis of bipolar disorder.

The hypothesis that one or more genes containing expanded trinucleotide repeats contribute to the pathogenesis of bipolar disorder has received support from three independent studies demonstrating that bipolar patients tend to have larger CAG/CTG repeat expansion detection products than controls. In an attempt to identify the specific expanded CAG/CTG locus or loci which are associated with bipolar disorder, we determined repeat size at CAG/CTG loci mapping to candidate regions for bipolar disorder. Recent linkage studies suggest the existence of a bipolar susceptibility gene on chromosome 12q23-q24.1 in the region of the Darier's disease (DAR) gene. In this study we report our findings from 11 loci which map to chromosome 12, including CAG repeat polymorphisms within the genes SCA2 and ASH1. We conclude that all of these loci are excluded as candidates for CAG/CTG repeat expansion in bipolar disorder.

Ataxins↗

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↗

PubMed2004

Comparative genetics of functional trinucleotide tandem repeats in humans and apes.

Several human neurodegenerative disorders are caused by the expansion of polymorphic trinucleotide repeat regions. Many of these loci are functional short tandem repeats (STRs) located in brain-expressed genes, and their study is thus relevant from both a medical and an evolutionary point of view. The aims of our study are to infer the comparative pattern of variation and evolution of this set of loci in order to show species-specific features in this group of STRs and on their potential for expansion (therefore, an insight into evolutionary medicine) and to unravel whether any human-specific feature may be identified in brain-expressed genes involved in human disease. We analyzed the variability of the normal range of seven expanding STR CAG/CTG loci (SCA1, SCA2, SCA3-MJD, SCA6, SCA8, SCA12, and DRPLA) and two nonexpanding polymorphic CAG loci (KCNN3 and NCOA3) in humans, chimpanzees, gorillas, and orangutans. The study showed a general conservation of the repetitive tract and of the polymorphism in the four species and high heterogeneity among loci distributions. Humans present slightly larger alleles than the rest of species but a more relevant difference appears in variability levels: Humans are the species with the largest variance, although only for the expanding loci, suggesting a relationship between variability levels and expansion potential. The sequence analysis shows high levels of sequence conservation among species, a lack of correspondence between interruption patterns and variability levels, and signs of conservative selective pressure for some of the STR loci. Only two loci (SCA1 and SCA8) show a human specific distribution, with larger alleles than the rest of species. This could account, at the same time, for a human-specific trait and a predisposition to disease through expansion.

Analysis of Variance↗

PubMed1996

Confirmation of association between expanded CAG/CTG repeats and both schizophrenia and bipolar disorder.

Recent studies have suggested that expanded CAG/CTG repeats contribute to the genetic aetiology of schizophrenia and bipolar disorder. However, the nature of this contribution is uncertain and difficult to predict from other known trinucleotide repeat diseases that display much simpler patterns of inheritance. We have sought to replicate and extend earlier findings using Repeat Expansion Detection in an enlarged sample of 152 patients with schizophrenia, 143 patients with bipolar disorder, and 160 controls. We have also examined DNA from the parents of 62 probands with schizophrenia or bipolar disorder. Our results confirm our earlier, preliminary findings of an association between expanded trinucleotide repeats and both schizophrenia and bipolar disorder. However, our data do not support the hypothesis that trinucleotide repeat expansion can alone explain the complex patterns of inheritance of the functional psychoses neither can this mechanism fully explain apparent anticipation.

Adult↗

PubMed2001

Anticipation, imprinting, trinucleotide repeat expansions and psychoses.

1. Since 1991, approximately 20 trinucleotide repeat expansion type neurodegenerative disorders have been reported. They are clinically characterized by anticipation, i.e., worsening severity or earlier age at onset with each succeeding generation for an inherited disease, and imprinting, i.e., a process whereby specific genes are differentially marked during parental gametogenesis, resulting in the differential expression of these genes in the embryo and adult. 2. The phenomenon of anticipation in psychoses has been pointed out since the 19th century; however, it was ignored because no one knew the genetic mechanism underlying this type of inheritance pattern at the time, and because of several possible biases. 3. The discovery of trinucleotide repeat expansion diseases has reawakened interest in the phenomenon of anticipation in psychiatric diseases. Anticipation has been confirmed in schizophrenia, mood disorders, and anxiety disorders in much more sophisticated manners, although still not perfectly. 4. Molecular approaches as well as clinical ones have been taken to reveal the involvement of trinucleotide repeat expansion mechanism in psychoses by means of direct analyses of candidate genes, RED and DIRECT. Most efforts have been made for CAG type trinucleotide repeats. So far, direct analyses have failed to reveal pathogenic gene(s). There were several positive RED data at first, however, nowadays there seems to be a tendency of much more negative results. The DIRECT results did not support trinucleotide repeat expansions mechanism in psychoses either. One plausable explanation for the 'false positive' result is the presence of CAG trinucleotide repeats which are highly polymorphic but not associated with an obvious abnormal phenotype. Screening for trinucleotide repeats other than ones of the CAG type remained to be performed.

Anticipation, Genetic↗

PubMed1999

A novel PCR-based approach for the detection of the Huntington disease associated trinucleotide repeat expansion.

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder associated with expansions of an unstable CAG trinucleotide repeat in exon 1 of the IT15 gene. In normal individuals, IT15 contains up to 35 CAG repeats, while in affected the repeat length is >36. Polymerase chain reaction (PCR) is used to estimate the number of CAG repeats but may be inefficient in long repeats because of the high C+G content of the HD locus. We present a novel PCR approach for the diagnosis of HD, which permits direct visualization of the amplified products on agarose gel, using ethidium bromide. It is based on the methylation-sensitive conversion of C residues to U by bisulfite treatment of single-stranded DNA and subsequent amplification of the sense strand with specific primers. The bisulfite treatment dramatically reduces the C + G content of the region; thus, the high Tm and stable secondary structures are no longer obstacles to PCR. In both normal and affected individuals, UAG repeats (5'- CAG-3', before bisulfite treatment) in the sense strand can easily be amplified and visualized on a gel by ethidium bromide staining. The method has considerable advantages compared with other described PCR-based diagnostic tests for HD.

Base Sequence↗

PubMed1995

Stability of an expanded trinucleotide repeat in the androgen receptor gene in transgenic mice.

The expansion of trinucleotide repeat sequences underlies a number of hereditary neurological disorders. To study the stability of a trinucleotide repeat and to develop an animal model of one of these disorders, spinal and bulbar muscular atrophy (SBMA), we have generated transgenic mice carrying either the normal or expanded repeat human androgen receptor (AR) gene. Unlike the disease allele in humans, the AR cDNA containing the expanded repeat in transgenic mice showed no change in repeat length with transmission. Expression of the SBMA AR was found in transgenic mice, but at a lower level than normal endogenous expression. The lack of a physiological pattern of expression may explain why no phenotypic effects of the transgene were observed.

Animals↗

PubMed1997

The complex pathology of trinucleotide repeats.

The expansion of trinucleotide repeat sequences has now been shown to be the underlying cause of at least ten human disorders. Unifying features among these diseases include the unstable behavior of the triplet repeat during germline transmission when the length of the repeat exceeds a critical value. However, the trinucleotide repeat disorders can be divided into two distinct groups. Type I disorders involve the expansion of CAG repeats, which encode an expanded polyglutamine, inserted into the open-reading frame of a gene that is usually quite broadly expressed. Recently, mouse models for type I disorders have been developed and the basis of pathology is under study, both in these models and through biochemical and cell biological approaches. The type II disorders involve repeat expansions in noncoding regions of genes. The mechanisms by which these repeat expansions lead to pathology may be quite diverse.

Animals↗

PubMed1997

Anticipation in schizophrenia: biology or bias?

Anticipation is a genetic phenomenon wherein age of disease onset decreases and/ or severity increases in successive generations. Anticipation has been demonstrated for several neuropsychiatric disorders with expanding trinucleotide repeats recently identified as the underlying molecular mechanism. We report here the results of an analysis of anticipation performed with multiplex families segregating schizophrenia. Thirty-three families were identified through the NIMH Genetics Initiative that met the following criteria: had at least two affected members in successive generations and were not bilineal. Affectation diagnoses included schizophrenia, schizoaffective disorder-depressed, and psychosis NOS. Additional analyses included the Cluster A personality disorders. Three indices of age of onset were used. Disease severity was measured by several different indices. Four sampling schemes as suggested by McInnis et al. were tested, as well as additional analysis using pairs ascertained through the parental generation. Anticipation was demonstrated for age of onset, regardless of the index or sampling scheme used (P<0.05). Anticipation was not supported for disease severity. Analyses that took into account drug use and diminished fecundity did not affect the results. While the data strongly support intergenerational differences in disease onset consistent with anticipation, they must be viewed cautiously given unavoidable biases attending these analyses.

Age of Onset↗

PubMed1997

Expanded CAG/CTG repeats in bipolar disorder: no correlation with phenotypic measures of illness severity.

The hypothesis that expanded trinucleotide repeats (TNRs) contribute to the pathogenesis of bipolar disorder has received strong support from recent studies showing that, on average, bipolar patients carry larger repeat sequences of the TNR motif CAG/CTG than do controls. It has been postulated that intergenerational expansion of a TNR may be responsible for the tendency for age of onset to become earlier in younger generations (anticipation) observed in some bipolar pedigrees, and that length polymorphism may account for variability in clinical phenotype. We have used the method of repeat expansion detection to examine these predictions in a sample of 133 Caucasian DSM-III-R bipolar I probands from the British Isles. We found no evidence to support the notion that CAG/CTG TNR genes are major determinants of phenotypic severity or age at onset in the population examined, and conclude that for most cases of bipolar disorder TNR genes may operate as susceptibility genes rather than as single genes of major effect.

Adult↗

PubMed1998

Absence of the fragile X CGG trinucleotide repeat expansion in girls diagnosed with a pervasive developmental disorder.

The purpose of this study was to determine the prevalence of the fragile X (FRAX) CGG trinucleotide expansion in a population of young girls (n = 45) diagnosed with pervasive developmental disorder (PDD). Their mean age was 43.7 months (range, 25 to 132 months). Diagnoses included autistic disorder (n = 20), PDD (n = 23), and Asperger's syndrome (n = 2). Molecular FRAX testing was performed on all patients by using the Southern gene blot technique. Genomic DNA was digested with both EcoRI and EagI, fractionated on agarose gel, and blotted and probed with the radiolabeled StB12.3 FMR-1 probe. None of the subjects were found to have an expansion of CGG in either the 2.8 kb or 5.2 kb fragments. A 95% CI, for the prevalence of the FRAX mutation in female subjects with PDD, has an upper bound of 2.9%. We conclude that the prevalence of FRAX positivity in girls with PDD is lower than previously reported. This raises the question of whether any association between FRAX and PDD in female subjects is specific to PDD or is related rather to the presence of mental retardation.

Autistic Disorder↗

PubMed1998

Evidence for two preferred hairpin folding patterns in d(CGG).d(CCG) repeat tracts in vivo.

Unusual DNA secondary structures have been implicated in the expansion of trinucleotide repeat tracts that has been found to be responsible for a growing number of human inherited disorders and folate-sensitive fragile chromosome sites. By inserting trinucleotide repeat sequences into a palindromic clamp in lambda phage we are able to investigate their tendencies to form hairpins in vivo in any particular alignment and with odd or even numbers of repeat units in the hairpin. We previously showed that with d(CAG).d(CTG) repeat tracts there was a markedly greater tendency to form hairpins with even numbers of repeat units than with odd numbers, whereas d(GAC).d(GTC) repeats showed no such alternation despite having the same base composition. We expected that d(CGG).d(CCG) repeats, might show the same pattern as d(CAG).(CTG) repeats since they are also involved in trinucleotide repeat expansion disorders. The pattern was not so clear and we wondered whether this might be because d(CGG).d(CCG) repeats have more than one possible alignment in which they could self-anneal. We now present results for all three alignments, which suggest that while even-membered hairpins are preferred in the frame d(CGG).d(CCG), hairpins with odd numbers of trinucleotides are more stable in the frame d(GGC).d(GCC). In both cases the base-pair predicted to close the terminal loop of unpaired bases is 5'C.3'G which has previously been found to be a favoured loop-closing pair.

Cytosine↗

PubMed1994

On the inheritance of the split hand/split foot malformation.

Analysis of families with non-syndromal split hand/split foot (SHSF) confirms the existence of 2 distinct entities, most probably caused by at least 2 different autosomal dominant genes. In the families in which the SHSF malformation is non-syndromal and limited to the hands and feet (type I), the pattern of inheritance is of a regular autosomal dominant gene with a high penetrance (96%). In families in which at least one individual has other limb malformations and SHSF (type II), the transmission is often unusual. In most families, the gene is non-penetrant, sometimes for generations, before the birth of the first affected individual. Thereafter, among the descendants of affected individuals, the penetrance is reduced (66%), suggesting the possible existence of another gene which controls the appearance of the clinical manifestations. The possibility that SHSF associated with other limb malformations is a disorder caused by trinucleotide repeat instability is raised.

Chromosomes, Human, Pair 7↗

PubMed2000

The unstable trinucleotide repeat story of major psychosis.

New hopes for cloning susceptibility genes for schizophrenia and bipolar affective disorder followed the discovery of a novel type of DNA mutation, namely unstable DNA. One class of unstable DNA, trinucleotide repeat expansion, is the causal mutation in myotonic dystrophy, fragile X mental retardation, Huntington disease and a number of other rare Mendelian neurological disorders. This finding has led researchers in psychiatric genetics to search for unstable DNA sites as susceptibility factors for schizophrenia and bipolar affective disorder. Increased severity and decreased age at onset of disease in successive generations, known as genetic anticipation, was reported for undifferentiated psychiatric diseases and for myotonic dystrophy early in the twentieth century, but was initially dismissed as the consequence of ascertainment bias. Because unstable DNA was demonstrated to be a molecular substrate for genetic anticipation in the majority of trinucleotide repeat diseases including myotonic dystrophy, many recent studies looking for genetic anticipation have been performed for schizophrenia and bipolar affective disorder with surprisingly consistent positive results. These studies are reviewed, with particular emphasis placed on relevant sampling and statistical considerations, and concerns are raised regarding the interpretation of such studies. In parallel, molecular genetic investigations looking for evidence of trinucleotide repeat expansion in both schizophrenia and bipolar disorder are reviewed. Initial studies of genome-wide trinucleotide repeats using the repeat expansion detection technique suggested possible association of large CAG/CTG repeat tracts with schizophrenia and bipolar affective disorder. More recently, three loci have been identified that contain large, unstable CAG/CTG repeats that occur frequently in the population and seem to account for the majority of large products identified using the repeat expansion detection method. These repeats localize to an intron in transcription factor gene SEF2-1B at 18q21, a site named ERDA1 on 17q21 with no associated coding region, and the 3' end of a gene on 13q21, SCA8, that is believed to be responsible for a form of spinocerebellar ataxia. At present no strong evidence exists that large repeat alleles at either SEF2-1B or ERDA1 are involved in the etiology of schizophrenia or bipolar disorder. Preliminary evidence suggests that large repeat alleles at SCA8 that are non-penetrant for ataxia may be a susceptibility factor for major psychosis. A fourth, but much more infrequently unstable CAG/CTG repeat has been identified within the 5' untranslated region of the gene, MAB21L1, on 13q13. A fifth CAG/CTG repeat locus has been identified within the coding region of an ion transporter, KCNN3 (hSKCa3), on 1q21. Although neither large alleles nor instability have been observed at KCNN3, this repeat locus has been extensively analyzed in association and family studies of major psychosis, with conflicting findings. Studies of polyglutamine containing genes in major psychosis have also shown some intriguing results. These findings, reviewed here, suggest that, although a major role for unstable trinucleotides in psychosis is unlikely, involvement at a more modest level in a minority of cases cannot be excluded, and warrants further investigation.

Anticipation, Genetic↗