Human Molecular Genetics, 2001, Vol. 10, No. 20 2187-2194
© 2001 Oxford University Press
Dynamic mutations: a decade of unstable expanded repeats in human genetic disease
Department of Molecular Biosciences, The University of Adelaide, Adelaide, SA 5000, Australia and Centre for Medical Genetics, Women’s and Children’s Hospital, North Adelaide, SA 5006, Australia
Received June 10, 2001; Accepted July 6, 2001.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMECHANISM OF DYNAMIC MUTATIONPATHOGENIC PATHWAYSCONCLUSIONSREFERENCES |
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The term ‘dynamic mutation’ was introduced to distinguish the unique properties of expanding, unstable DNA repeat sequences from other forms of mutation. The past decade has seen dynamic mutations uncovered as the molecular basis for a growing number of human genetic diseases and for all of the characterized ‘rare’ chromosomal fragile sites. The common properties of the repeats in different diseases and fragile sites have given insight into this unique form of DNA instability. While the dynamic mutation mechanism explains some unusual genetic characteristics, unexpected findings have raised new questions and challenged some assumptions about the pathways that lead from mutation to disease. This review will address the current understanding of the molecular mechanisms involved in the dynamic mutation process and elaborate on the pathogenic pathways that lead from expanded repeats to the diseases with which they are associated.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMECHANISM OF DYNAMIC MUTATIONPATHOGENIC PATHWAYSCONCLUSIONSREFERENCES |
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Ten years ago the first reports appeared (1,2) of expanded DNA repeat sequences being the molecular basis of human genetic diseases—fragile X syndrome and spino-bulbar muscular atrophy (Kennedy disease). In both cases a simple DNA repeat sequence (CCG or CAG), which varied in copy number in normal individuals, was found to be increased in copy number beyond a certain threshold in affected individuals. Given the idiosyncratic nature of these diseases, particularly fragile X syndrome (3), it could have been that these expanded repeats were manifestations of an uncommon mechanism with characteristics peculiar and unique to their associated diseases. Instead, however, an ever-growing list of human diseases and chromosomal fragile sites has identified dynamic mutation as an important mechanism in human genetics. Consequently, both the molecular processes underlying this form of mutation and the pathogenic pathways leading from the mutation to its phenotype have been the subject of intense investigation. Over the past decade numerous reviews have updated the progress of these investigations (4–10). Rather than reiterate this progress, the purpose of this review is to identify the generally accepted principles underlying dynamic mutation and to discuss those areas where the current understanding is either lacking or clouded by apparently conflicting observations.
Comparative anatomy has long been a potent tool to develop an understanding of the functional or mechanistic basis responsible for a particular physical phenomenon. The application of comparative molecular anatomy to the study of different classes of chromosomal fragile sites and to the diseases caused by DNA repeat expansion has led to the identification of a number of common properties that most likely reflect common molecular mechanisms for both the genesis of expanded repeats and the molecular pathways from repeat expansion to disease phenotype. These general properties include: (i) mutation manifests as a change (usually increase) in repeat copy number with mutation rate related to the initial copy number of the repeat; (ii) rare ‘founder’ events (such as loss of repeat interruption) lead to alleles with increased likelihood of undergoing changes in repeat copy number; and (iii) the diseases caused by repeat expansion exhibit a relationship between copy number of the repeat and the severity and/or age-at-onset of symptoms. These properties together account for anticipation, the increasing severity/incidence and/or decreasing age-at-onset in successive generations within an affected family. However, an increasing number of exceptions and unexpected findings suggest that early conclusions, particularly in regard to possible common pathogenic mechanisms, may have been premature.
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MECHANISM OF DYNAMIC MUTATION |
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TOPABSTRACTINTRODUCTIONMECHANISM OF DYNAMIC MUTATIONPATHOGENIC PATHWAYSCONCLUSIONSREFERENCES |
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The process of dynamic mutation is affected by a variety of elements and factors that have been divided into those directly associated with the expanding repeat (cis-acting elements) and those (trans-acting factors) whose interaction with the repeat contributes to its instability. Examples of cis-acting factors include the copy number and the composition of the repeat (whether it is perfect or interrupted) (11). In general, higher copy number alleles that are free of interruptions (perfect repeats) are more unstable than those of lower copy number and/or contain interruptions (imperfect repeats). While there is indirect evidence for the existence of trans-acting factors (such as parental gender bias in repeat instability), the identity of these factors remains elusive. Candidates include the proteins involved in DNA replication such as FEN1 (Rad27), which is known to have a role in Okazaki fragment metabolism (12).
What kinds of repeat sequences undergo dynamic mutation?—Cis-acting factors
The first expanded repeats to be identified were the trinucleotides CCG/CGG and CAG/CTG. Initially this was taken as evidence that only trinucleotide repeats could undergo this form of mutation (which was sometimes referred to as trinucleotide repeat expansion). Furthermore, since these two repeats could form secondary structures, it was assumed that this was also a necessary condition for repeat instability (13). Subsequently, six of the ten possible trinucleotide repeats have been found to exhibit repeat expansion in humans (14), and, more recently, 5 and 6 bp microsatellite repeats (15,16) and 12, 33 and 42 bp minisatellite repeats (17–19) have also been observed to undergo repeat copy number expansion.
Founder effects are observed in association with dynamic mutation as a higher frequency of particular alleles in the affected population, compared with the unaffected population, suggesting that these alleles are ‘at-risk’ for mutation. The likelihood is that the initial mutation on these alleles is a rare event that increases the instability of the repeat, setting in process the subsequent expansion of these few founder mutations. Founder effects (Table 1) are a common feature of dynamic mutation and in many cases common flanking marker haplotypes provide evidence of a relationship between the expanded alleles and the longest normal (usually uninterrupted) alleles in the population. Therefore a common molecular mechanism appears to be responsible (Fig. 1).
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At the FRAXA locus, detailed haplotyping studies, together with sequence analysis of different repeat alleles, have provided evidence in support of the view that certain alleles are predisposed to instability (11,20). Similar analyses in other populations suggest that such differences are likely to be population-specific rather than indicative of a molecular pathway predisposed by cis-acting elements in and around the FRAXA repeat (21,22). One possible explanation for the inconsistency here is that chance has a role to play and that the differences between populations merely reflect the different rare initial events that have precipitated the dynamic mutation process. Given that there are multiple possibilities for generating an unstable repeat then different populations are likely to have different combinations and/or frequencies of these unstable alleles. Thus, in terms of understanding the mutation process, caution is needed when extrapolating the results observed in one population to the human species as a whole.
What factors contribute to repeat DNA expansion?—Trans-acting factors
Gender bias in the instability of repeats during their transmission from parent to offspring is a common property of dynamic mutations. Most cases of the congenital form of myotonic dystrophy are maternally inherited, while the juvenile onset Huntington disease is generally from paternal inheritance. The gender of the germ line clearly contributes to these biases; however, the identity of the factors involved remains obscure.
Other factors that interact in some way with the repeat are also thought to contribute to repeat instability. A variety of circumstantial evidence (particularly from studies in model systems) suggests that Okazaki fragments may have a role to play in the expansion of DNA repeats. Several of the repeats (e.g. CCG in FRAXA and CAG in DM) exhibit a bimodal distribution of instability with the boundary between small changes and large changes in copy number approximating Okazaki fragment length. In Escherichia coli (which has a substantially longer Okazaki fragment length), this boundary is increased in copy number again to that approximating Okazaki fragment length (23). The secondary structure of CAG/CTG and CGG repeat sequences has been found to inhibit Okazaki flap endonuclease (FEN1) binding and cleavage (24). In addition, the FEN1 homologue, Rad27, has a role to play in DNA repeat instability in yeast. Yeast Rad27 mutants are prone to both DNA breakage and copy number instability of repeat sequences (25 and personal communication).
Contradicting the proposed role of DNA replication, Kennedy and Shelbourne (26) found dramatic expansion of the CAG repeat in the striatum of a transgenic mouse HD model. These neurons are presumably no longer undergoing cell division, indicating that expansion is occurring independently of DNA replication. Similarly, Kotvun and McMurray (27) have found that germ-line trinucleotide repeat sequence expansion in transgenic mice also proceeded in the absence of DNA replication via gap repair. Perhaps, given that DNA instability is occurring at the repeat sequence in the absence of replication, some form of transcriptional healing may be contributing to the repeat expansion process (28). Transcriptional healing has been invoked in the fragile site expression of tandemly repeated small RNA transcripts (29). In further support of a role for breakage and repair Manley et al. (30) have found that Msh2 is required for CAG repeat somatic cell instability in an HD transgenic mouse.
Age-dependent somatic cell instability of the CTG repeat sequence has been found in myotonic dystrophy (31), although here it is not confined to those cells that are affected in the disease and in fact gives a growth advantage to lymphoblastoid cell lines that have undergone expansion (32).
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PATHOGENIC PATHWAYS |
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TOPABSTRACTINTRODUCTIONMECHANISM OF DYNAMIC MUTATIONPATHOGENIC PATHWAYSCONCLUSIONSREFERENCES |
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Loss of function/haploinsufficiency
Extinction of, or interference with transcription is one means by which expanded repeats cause loss of gene function. Examples are: fragile X syndrome, in which repeat expansion brings about methylation of the FMR1 promoter region (33); myoclonus epilepsy (EPM1) (34), in which repeat expansion physically separates transcription factors in the cystatin B promoter; and Friedreich ataxia, in which the intronic expanded repeat sequence adopts a ‘sticky’ DNA structure that interferes with transcription of the frataxin gene (35). While these resultant diseases exhibit recessive (or X-linked) transmission, the potential exists for dominant transmission where reduction in the level or activity of a rate limiting gene product can appear as haploinsufficiency. This appears to be the case for the SIX5 gene in myotonic dystrophy (36,37), as the expanded CTG repeat is located in the SIX5 promoter. The reduction in effective ‘dosage’ of the SIX5 gene product brought about by extinction of one allele is thought to contribute to some aspects of pathology (see below).
Gain of function: the toxic polyglutamine hypothesis—old concerns about a new dogma
Numerous expanded repeat sequences are located within coding regions where they translate into expanded polyglutamine tracts in disease alleles (Table 2). This, together with a substantial body of data demonstrating the toxicity of polyglutamine in cells, has led to the view that the expanded polyglutamine is a common, crucial component in the pathogenesis of these diseases. In support of this view, an antibody, 1C2, raised against the normal length polyglutamine tract of the TATA-box binding protein (TBP), was found to specifically recognize the expanded polyglutamine in several of the expanded repeat diseases, e.g. huntingtin, ataxin 1 and others (38). This was taken as evidence that the expanded polyglutamine adopted a different conformation that in some way contributed to its toxicity. The context in which the repeat sequence was located was proposed to account for why such an otherwise toxic conformation did not cause problems when located within TBP. This theory is now somewhat flawed, as the expanded polyglutamine tract in some alleles (n >50) of TBP has recently been associated with neurodegenerative disease (39,40). It is possible that yet another conformation of the expanded polyglutamine tract is adopted once the repeat sequence gets beyond an even greater threshold.
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Nuclear inclusions were found in the affected neurons of HD and SCA1 transgenic mouse models and HD patients (41), prompting the assertion that these expanded polyglutamine-containing nuclear inclusions cause neuronal dysfunction. Klemment et al. (42) deleted the SCA1 self-association region in transgenic mice and found that these mice still exhibited ataxia and Purkinje cell pathology; however, no evidence of nuclear aggregates was found. Other studies on the brains of individuals affected with Huntington’s disease (43,44) revealed that nuclear aggregates were more commonly found in unaffected neurons than in the vulnerable striatal spiny neurons. Consequently, it has now been proposed that rather than being pathogenic, nuclear inclusions may even be protective against the toxic effects of the expanded polyglutamine (45).
Further conflicting evidence to a common role for polyglutamine in pathogenesis is that disease alleles of the CAG repeat in spinocerebellar ataxia 6 are well within the normal range for other ‘polyglutamine diseases’. Functional assays on expanded CAG alleles of the SCA6 associated gene, CACNA1A, demonstrate increased Ca2+ transport (46) and thus make it likely that this gain of function is a specific and unique cause of pathogenesis for this disorder. Taken together, these exceptions suggest that the notion of a common single pathogenic pathway involving polyglutamine is unlikely.
As if contradictions with polyglutamine encoding genes are not enough, a growing list of repeat-associated ataxias do not even encode polyglutamine (Table 2). In SCA12, the expanded CAG repeat is located within the 5'-untranslated region (5'-UTR) of the PPP2R2B gene (47,48), while in SCA8 an expanded CUG is located within the 3'-UTR of a transcript (although there is controversy over whether this expansion is causative of neurodegenerative disease) (49–51). In addition, an intronic expanded 5 bp repeat was recently found to be associated with SCA10 (15).
So the question must be asked whether expanded polyglutamine is a necessary and sufficient condition for those diseases in which it has been identified as the disease-causing agent. If it is, then how is the cellular specificity of this toxicity accounted for when at least some of these proteins are widely expressed (see 52)? One possible explanation for this conundrum comes from the findings of Kennedy and Shelbourne (26), which reveal affected cell-specific amplification of the unstable CAG repeat in a mouse model of Huntington’s disease. Individuals affected with Huntington’s disease have also been found to exhibit somatic instability, which was most pronounced in the affected areas of the brain (53,54). This suggests that ongoing somatic mutation may contribute to diseases caused by expanded repeats. This expansion may also account for the relationship between germ-line repeat copy number and age-at-onset for these diseases (7). The time taken for the disease to manifest could represent how long it takes for the disease-associated allele to reach a critical higher copy number threshold in the affected cell population (Fig. 2).
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What then is the evidence that polyglutamine has a role? The principal data are from transgenic animal model studies, particularly those from SCA1 transgenic mice. Mutation of the ataxin-1 nuclear localization signal severely diminishes toxicity, whereas abolition of sequences necessary for aggregation does not (42). Crossing of SCA1 mice with a transgenic mouse deficient in ubiquitin ligase results in more severe pathology (55). For SCA2 and SCA6, nuclear localization does not appear to be necessary, suggesting different pathways than that for SCA1 (and HD) (56,57).
In an HD transgenic mouse model where transcription of the transgene could be artificially turned on or off, expression of the expanded CAG-containing gene was elegantly demonstrated to be necessary for HD-like pathology (58). This animal model provides the first indication that HD (and hopefully other expanded CAG repeat diseases) is potentially treatable—given that, in those patients at risk, the disease-causing gene can either be switched off or the toxic gene product can be cleared from the sensitive neurons.
Presumably other factors, such as modification of the polyglutamine tract and/or the protein context in which the polyglutamine is located, contribute to the cellular specificity of toxicity. Examples of where this apparently is (59) or is not (60) the case have been reported. The relative contribution of various intrinsic and extrinsic factors is therefore likely to differ between the different disease genes (and experimental model systems). Genetic screens for factors that modify polyglutamine-generated pathology in Drosophila have produced a large number and variety of candidates (61,62), and it will be of great interest to see which (if any) of these has a role in human polyglutamine disease.
Bias of ascertainment was invoked by Penrose to account for (and discredit) the observation of anticipation seen by clinical geneticists in myotonic dystrophy families (63). While expanded DNA repeats now give a molecular basis (and validation) for the phenomenon of anticipation, the relative ease with which expanded CAG repeats can be screened for as a cause of neurodegenerative disease may well have led to an overemphasis of the relative importance of this form of mutation and perhaps contributed to the view that expanded CAG repeats necessarily have a common pathogenic pathway (via their encoded expanded polyglutamines). While there is a substantial body of evidence in support of a role for polyglutamine in some repeat expansion diseases there is a growing list of exceptions and inconsistencies which suggest (at the least) that this is not necessarily a common pathogenic pathway exhibited by all neurodegenerative diseases in which an expanded repeat (let alone an expanded CAG) is the disease-causing mutation.
Further evidence for alternative pathways—multiple gene effects
In myotonic dystrophy there is good evidence to support not only a role for multiple genes, but also multiple pathways in mediating the pathogenic effects of repeat expansion (for review see 10). Three genes (DMPK, SIX5 and DMWD) are all located in the immediate vicinity of the DM expanded CTG repeat. At least three distinct pathogenic pathways are thought to contribute to DM. (i) The expanded repeat affects the splicing of the DMPK gene in which it is located (64). (ii) The RNA transcript containing the expanded repeat is both inappropriately compartmentalized and titrates a crucial protein (muscleblind) (65). Expression of the CTG repeat in another muscle-specific transcript is able to cause at least some of the DM phenotype (myotonia and myopathy) (66). (iii) The DM CTG repeat is also located in the promoter region of the SIX5 gene and its expansion also interferes with the expression of this gene. The SIX5 gene encodes a transcription factor whose concentration is critical for eye, muscle and testicular development (67). Heterozygous deletion of Six5 is sufficient to cause ocular cataracts in transgenic mice (36,37), and therefore the SIX5 haploinsufficiency brought about by the DM CTG repeat expansion is likely to contribute to the DM phenotype.
The FRAXE chromosomal fragile site is associated with a mild form of mental retardation (68). The expanded CCG repeat was first initially located in the 5'-UTR of a gene, referred to as FMR2. The expression of FMR2 is extinguished by repeat expansion and subsequent methylation of the CpG island promoter region (69), in a manner analogous to the silencing of the FMR1 gene at the FRAXA locus in fragile X syndrome (33). It was therefore thought that the loss of FMR2 was responsible for the phenotype associated with FRAXE. However, an additional gene, FMR3, has now been identified that shares the same methylated CpG island (70). Expression of FMR3 is also silenced by FRAXE full mutation and therefore this gene may also contribute to the phenotype.
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CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONMECHANISM OF DYNAMIC MUTATIONPATHOGENIC PATHWAYSCONCLUSIONSREFERENCES |
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Given that increasing the copy number of existing DNA repeat sequence would appear to be a relatively simple process, in reality the biological causes and consequences of such phenomena can be remarkably complex. In fact, a major issue in understanding both the process of dynamic mutation and the pathway from genotype to phenotype is being able to distinguish between cause and consequence. It certainly appears as though there are multiple components to the mutation process and it is clear that there can be multiple pathways to the resultant disease (Fig. 3). So far dynamic mutations have been detected in diseases (and at fragile site loci) with very high penetrance. It will be intriguing to see whether DNA repeats also contribute to multifactorial diseases and disease susceptibility.
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ACKNOWLEDGEMENTS |
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I thank Keith Johnson, Catherine Freudenreich and Alec Jeffreys for communicating data prior to publication and Kathryn Friend, Sonia Dayan, Merran Finnis and Lynne Hobson for constructive comments on drafts of this review. I am grateful to Shelley Richards for her support and encouragement. The preparation of this review was supported by grants from the Anti-Cancer Foundation of South Australia and the National Health and Medical Research Council of Australia.
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FOOTNOTES |
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+ To whom correspondence should be addressed at: Department of Molecular Biosciences, The University of Adelaide, Adelaide, SA 5000, Australia. Tel: +618 8303 7541; Fax: +618 8303 4362; Email: robert.richards@adelaide.edu.au
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