Fragile X syndrome : repeating elements within DNA cause neurodegenerative diseases


Over half of our genomes are made of repeating elements within DNA.

In rare cases, these repeats can become unstable and grow in size. These repeat “expansions” cause neurodegenerative diseases such as ALS and dementia as well as learning disorders and autism in Fragile X syndrome.

Research to date has focused on how these expanded repeats cause disease, but little attention has been given to the repeats themselves and whether they might have normal functions in genes.

By focusing on the biology of healthy nerve cells, a Michigan Medicine team found that repeats in the gene that causes Fragile X Syndrome normally regulate how and when proteins are made in neurons.

This process may be important for learning and memory in these nerve cells and potentially in people.

“The repeats function like a switch, slowing down protein production and then quickly turning things back on,” explains principal investigator Peter Todd, M.D., Ph.D., associate professor of neurology at Michigan Medicine.

This study first used rodents and then created human neurons from patient stem cells.

The scientists found that the repeat and its translation in the beginning of the Fragile X gene slow down production of the Fragile X protein, which is important in learning and memory.

However, when neurons are stimulated, this repeat translation goes away and the Fragile X protein levels increase at synapses (the connections between nerve cells), suggesting that the repeat and its translation regulate this local protein production.

By focusing on the biology of healthy nerve cells, a Michigan Medicine team found that repeats in the gene that causes Fragile X Syndrome normally regulate how and when proteins are made in neurons.

This process may be important for learning and memory in these nerve cells and potentially in people. Image is in the public domain.

Armed with this discovery about how the repeat functions normally, the team worked with Ionis Pharmaceuticals to develop an antisense oligonucleotide (ASO), a short strand of modified DNA that can specifically target the transcripts of a defective gene to correct an abnormality.

Ionis’ ASOs are designed to bind precisely with RNA, halting the process of creating a disease-causing protein which could block translation of expanded Fragile X repeats that are toxic to neurons and cause human disease.

This ASO has produced two remarkable results. First, it decreased the toxicity that these repeats caused in rodent and human neurons.

Second, this blockade of repeat translation triggered a big increase in the Fragile X protein, whose loss causes Fragile X syndrome.

“The results suggest that we have simultaneously corrected two of the big problems that happen in Fragile X-associated disorders,” Todd says.

This research offers a novel pathway forward to treatments in this class of neurological diseases.

“To develop a new treatment strategy, we really needed to understand the native biology of how these repeats work and why they are there in the first place,” says Todd.

“The study was done in dishes, and so there is still a long way before it can be tried in patients, but advancing our understanding of normal nerve cell biology is a crucial step to find cures.”

Microsatellites, also known as simple sequence repeats or tandem repeats, are normally polymorphic nucleotide sequences scattered throughout the human genome.

Although such repeats have long been used in linkage studies to define the genetic basis of human diseases, it only became clear over the past several decades that expansions of simple sequence repeats directly cause many human diseases.

The vast majority of so-called repeat expansion diseases primarily affect the nervous system. Here I discuss general features of the repeat expansion diseases most relevant to neurologists, emphasizing their distinctive features that stem from the dynamic nature of the underlying mutations.

Because there are more than two dozen such diseases, they cannot all be discussed in detail. For more information on specific repeat expansion diseases, I refer the reader to definitive chapters in this volume on Fragile X Syndrome and Fragile X Tremor Ataxia Syndrome (FXS/FXTAS; chapter 25), the CAG/polyglutamine diseases (chapter 11), spinal and bulbar muscular atrophy (SBMA; chapter 38), Huntington disease (HD; chapter 17), the dominantly inherited ataxias known as the spinocerebellar ataxias (SCAs; chapter 12), the recessive disorder Friedreich ataxia (chapter 13 on recessive ataxias), C9ORF72 frontotemporal dementia/amyotrophic lateral sclerosis (chapter 27 on ALS), and Unverricht-Lundborg myoclonic epilepsy (EPM1; chapter 30 on genetic epilepsies).

This review does not cover the class of congenital neurocognitive disorders caused by polyalanine-encoding expansions (125), but does discuss oculopharyngeal muscular dystrophy (OPMD), an adult onset neuromuscular disorder caused by polyalanine expansion.

The discovery of dynamic repeat expansions shattered the conventional rules of Mendelian inheritance.

These rules posit fixed (static) mutations that cause disease through an autosomal dominant, autosomal recessive, or X-linked mechanism, yielding a similar phenotype within families and across generations.

In contrast, expanded repeats are unstable (dynamic) mutations that often change size in successive generations.

Moreover, depending on the size of the mutation, repeat expansion diseases can manifest with markedly varied phenotypes. Nearly all are primarily neurological diseases and some are among the most common genetic disorders seen by a neurologist. Thus, this category of diseases, unheard of 30 years ago, is now well known to neurologists.

The first nine repeat expansions discovered were all trinucleotide repeats, suggesting that this repeat unit might be a constant feature of this new class of diseases (107).

As Table 1 shows, however, new genetic discoveries revealed that the size of repeats ranges from trinucleotides (the vast majority) to tetranucleotides (DM2), pentanucleotides (SCA10, SCA31), hexanucleotides (C9ORF72FTD/ALS, SCA36) and even dodecanucleotides (EPM1). Additional repeat expansion diseases likely will be discovered that further widen the range of sequence repeats underlying human disease.

Table 1.

Repeat expansions causing neurologic disease

• CAG – at least 10 diseases (Huntington disease, spinal and bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy and seven SCAs)
• CGG – fragile X, fragile X tremor ataxia syndrome, other fragile sites (GCC, CCG)
• CTG – myotonic dystrophy type 1, Huntington disease-like 2, spinocerebellar ataxia type 8, Fuchs corneal dystrophy
• GAA – Friedreich ataxia
• GCC – FRAXE mental retardation
• GCG – oculopharyngeal muscular dystrophy
• CCTG – myotonic dystrophy type 1
• ATTCT – spinocerebellar ataxia type 10
• TGGAA – spinocerebellar ataxia type 31
• GGCCTG – spinocerebellar ataxia type 36
• GGGGCC – C9ORF72 frontotemporal dementia/amyotrophic lateral sclerosis
• CCCCGCCCCGCG – EPM1 (myoclonic epilepsy)

Despite their diversity, repeat expansion diseases share numerous features that stem from the underlying genetics (Table 2). All repeat expansions, for example, arise from normally polymorphic repeats in the population.

The degree of polymorphism among normal repeats ranges from disease to disease. But in general, repeats at the high end of the normal range (“mutable normal” repeats) have an increased propensity to further expand upon transmission, moving into the pathogenic range. This means that de novo mutations can occur in previously unaffected families.

A small percentage of HD, for example, is sporadic (e.g. 98), and the same is true for numerous autosomal dominant repeat expansion diseases. An important implication of this fact is that a patient showing features consistent with a certain repeat expansion disease, yet lacking a family history of similar disease, may still harbor the mutation.

Thus, in the right clinical setting the absence of a documented family history should not dissuade the physician from performing a genetic test to confirm or exclude the suspected diagnosis.

Table 2.

General features of repeat expansion diseases

• Arise from normally existing polymorphic repeats
• Expansions are unstable (dynamic), often changing size when transmitted to next generation
• Longer repeats tend to cause more severe, earlier onset disease
• Clinical anticipation is common: earlier onset, more severe disease in successive generations
• Highly variable phenotype, primarily reflecting differences in repeat size

Repeat expansions are inherently dynamic, often changing size when transmitted to the next generation. As a result, even in the same family, the phenotypic range of disease in affected individuals can vary remarkably.

The degree of within-generation and across-generation change varies among the disorders, in part because the size of expansions varies from less than 30 repeats (e.g. OPMD, SCA6) to upwards of one or several thousand repeats (e.g. DM1, DM2, FXS, SCA10, SCA36). 

Figure 1 shows a schematic of a gene into which various repeat sequences underlying repeat expansion diseases have been placed according to their known location in their respective disease genes. Some reside in the 5’ or 3’ untranslated regions (UTR), others in protein-coding exons, and still others in introns.

In figure 1, the markedly different sizes of pathogenic expansions are suggested by the varying sized triangles associated with each identified disease.

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Schematic of gene showing repeat expansions that cause neurological diseasesRepeat sequences linked to the indicated diseases are placed schematically into the appropriate gene locations. The differing sizes of the associated triangles roughly reflect the range of repeat expansion sizes in each disease. *SCA12 repeat is actually in an intron that also has promoter elements.

The diseases tend to show a striking genotype-phenotype correlation between repeat length and disease severity. The longer the repeat, the more severe the disease and the earlier the onset of symptoms.

This is particularly well illustrated for the CAG/polyglutamine diseases, nine disorders in which relatively modest CAG repeat expansions encode abnormally long stretches of glutamine in the respective disease proteins.

In all nine CAG/polyglutamine diseases, there is a strong inverse correlation between repeat length and age of symptom onset: longer repeats cause earlier disease that usually has more profound signs and symptoms (3,36,40,59,62,66,70,75,108,115,122,126,129).

The size of the expanded CAG repeat is itself the key determinant for age of onset, accounting for 45% to 70% of the effect, depending on the specific disease. The remaining contribution to age of onset comes from other, minor genetic modifiers and environmental factors that remain under investigation.

The relationship between repeat size and age of onset/disease severity is also robust for DM1, Friedreich ataxia, FXS/FXTAS, and several of the non-polyQ SCAs caused by expanded repeats. In contrast, the correlation between repeat length and disease severity in SCA8 is much less robust, and in DM2 and C9ORF72-mediated ALS/FTD is weak if present at all.

Intriguingly, all three of these latter diseases are caused by often quite large and complex repeats, suggesting that still unidentified molecular features at these loci influence the behavior of the pathogenic repeats.

Repeat expansion diseases typically show clinical anticipation – that is, the tendency for disease severity to increase in successive generations of a family.

This phenomenon had been noted by astute physicians long before the mutational basis was discovered but had been dismissed as biologically implausible; perhaps, doubters argued, the apparent worsening of disease across generations was merely the byproduct of detection bias.

The discovery of expanded repeat mutations, and the recognition that expanded repeats are inherently dynamic with longer repeats tending to be increasingly unstable, shed new light on the phenomenon.

We now understand that anticipation is explained by the tendency for expanded repeats to further enlarge upon transmission to the next generation, coupled with the fact that longer expansions tend to cause earlier onset, more severe disease.

The extent of anticipation and the degree to which there are parent-of-origin effects influencing anticipation vary across the diseases.

For example, several CAG/polyglutamine diseases show a marked paternal effect. Children born to fathers harboring a mutation in HD, SCA2 or SCA7, for example, may develop disease much earlier than their father, in some cases even before the father has developed symptoms (e.g. 138,140).

In contrast, the most severe form of myotonic dystrophy type I (DM1), congenital myotonic dystrophy, is almost always transmitted from the mother (6,141). Not all repeat expansions diseases show significant anticipation or a clear parent of origin effect. OPMD, for example, does not show anticipation, which may reflect the exceptionally small expansion size in this disease.

The mode of inheritance varies among the repeat expansion diseases. While the majority are inherited in an autosomal dominant manner, at least two are autosomal recessive (Friedreich’s ataxia and EPM1), two are X-linked recessive (FXS, FRAXE mental retardation) and two are X-linked yet have a dominant toxic mechanism of action (FXTAS and SBMA). The differing modes of inheritance reflect different molecular mechanisms of disease, discussed in the next section.

Arguably, the most striking feature about repeat expansion diseases is the markedly diverse phenotypes manifested for a given disease.

This varied phenotype principally reflects differences in repeat size. In HD, for example, whereas most affected individuals develop midlife chorea with cognitive and psychiatric symptoms, individuals with the longest repeats can manifest in their teens or even earlier with bradykinesia and dystonia rather than chorea (so called Westphal or juvenile onset variant of HD).

Likewise, another CAG/polyglutamine disorder, dentatorubral-pallidoluysian atrophy (DRPLA), can manifest early in life with dystonia, epilepsy and cognitive impairment or later with chorea and ataxia, again primarily reflecting differences in the size of the expansion.

Originally described in Japan, the DRPLA mutation was soon also discovered to be the cause of Haw-River syndrome in the United States, which had been thought to be a distinct disorder because it is characterized by seizures, brain calcifications and ataxia (18,75,90).

In DM1, the shortest pathogenic repeats can manifest simply with cataracts and late-life myotonia whereas the longest repeats cause congenital myotonic dystrophy with profound weakness and cognitive impairment.

In Friedreich ataxia, the “classic” form of disease typically begins before age 25 with the hallmark features of progressive ataxia, sensory loss and areflexia, but individuals with the smallest expansions may not develop symptoms until quite late in life and can even manifest with spasticity and hyperreflexia rather than areflexia (37a).

In SCA3, also known as Machado Joseph disease, disease features vary so much that clinicians have even categorized the disease into subtypes: Type I, early onset with dystonia; Type II, midlife onset with progressive ataxia and brainstem signs; and Type III, late life onset with distal leg weakness caused by motor neuronopathy and milder ataxia (37b). 

Figure 2 shows the range of disease repeats in SCA3, mapped onto these distinct subtypes, as well as a possible fourth phenotype: restless leg syndrome in individuals with intermediate expansions (a rare occurrence).

The key determinant driving these distinct subtypes in SCA3 is disease repeat length, with the aging process itself likely being an additional superimposed factor in this, and other, CAG/polyglutamine diseases (e.g. 115).

Similar graphs that map disease features and severity across the disease repeat range can be drawn for all of the CAG/polyglutamine diseases, as well as for most other repeat expansion diseases.

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Relationship of repeat length to disease features in spinocerebellar ataxia type 3 (SCA3)Normal CAG repeat length in SCA3 is 12 to ~44, with disease repeats ranging from ~60–87. Clinical subtypes 1 (dystonia), 2 (ataxia), and 3 (weakness) tend to be associated with the range of indicated repeat lengths. Rare intermediate repeat lengths may be associated with restless legs syndrome.

The Diseases

Here I briefly describe individual diseases or groups of related repeat expansion diseases, presented roughly in the chronological order of their discovery. I remind the reader that this neurogenetics volume includes definitive chapters that provide much more information on specific diseases. I also refer the reader to GeneReviews for up-to-date reports on nearly all repeat expansion diseases.

Fragile X syndrome (FXS), fragile X tremor ataxia syndrome (FXTAS), and other fragile X sites 

FXS is named after the folate-sensitive fragile site at the FRAXA locus on the X chromosome. The most common cause of inherited mental retardation, FXS typically affects males, varies greatly in severity, and is associated with dysmorphic features including enlarged head, ears and testicles (see chapter 25 in this volume for a more thorough description).

Scientists were puzzled for years that the risk of FXS increased from one generation to the next. Indeed, this particular example of anticipation carried its own name, the Sherman paradox.

The discovery in 1991 that FXS and its underlying fragile site are caused by an expanded CGG repeat that changes size over generations explained the paradox. Normal-sized repeats are polymorphic, ranging from 6 to 52, with repeats at the high end of this range being increasingly prone to further expand (“mutable normal”).

In FXS families the repeat sizes span a wide range, from “premutations” of ~60–200 repeats (typically found in maternal grandfathers) to full mutations of several thousand repeats (found in affected FXS males). The mothers of affected FXS males have variably sized expansions and are prone to premature ovarian failure.

As described earlier, the molecular mechanism of FXS is a loss of expression of the developmentally important nervous system protein, FMRP.

Full expansions promote hypermethylation of the FMR1 promoter and reduce translation of the transcript, effectively silencing expression the gene (12,39,103,130). Further supporting a loss of function as the basis of disease is the fact that some FXS is caused by inactivating mutations rather than a CGG expansion (33,47).

Maternal grandfathers of affected FXS males, who typically harbor a premutation allele, are at risk for developing FXTAS (53).

This late-life neurodegenerative disorder is characterized by progressive ataxia, essential-type tremor, cognitive impairment and occasionally parkinsonism.

Brain imaging often shows T2-weighted signal abnormalities in the middle cerebellar peduncles as well as more generalized brain atrophy. In males with late-life, progressive cognitive impairment, imbalance and incoordination who have a grandson with mental retardation, screening for the FXS/FXTAS repeat expansion should be considered.

In FXTAS, the premutation does not silence the gene but instead permits continued expression of the FMRP transcript. The transcript may even accumulate to higher levels than normal, and is thought to cause disease through a combination of toxic RNA and toxic protein effects linked to RAN translation (137), as discussed earlier.

Numerous other fragile sites are caused by GC-rich trinucleotide expansions, in some cases associated with mental retardation. These include FRAXE mental retardation (GCC), as well as the FRAXE(GCC) and FRA16A (CCG) fragile sites (e.g. 72106).

Myotonic dystrophy types 1 and 2 (DM1, DM2) 

Myotonic dystrophy is an autosomal dominant multi-system disease characterized principally by myotonic myopathy. There are two major forms of myotonic dystrophy, both caused by repeat expansions. DM1, also known as Steinert disease, is caused by a CTG expansion in the 3’UTR of the DMPK gene (7,16,43,54).

DM2, which is much less common than DM1 and was previously known as proximal myotonic myopathy, is caused by a CCTG repeat in intron 1 of theCNBP gene (formerly named ZNF9)(84). Despite their similarities, DM1 and DM2 differ in important molecular and clinical respects. Most importantly, DM1 shows robust repeat length/disease severity correlation as well as significant anticipation, whereas DM2 does not.

DM1 is characterized by progressive weakness and myotonia, often associated with cataracts, cardiac arrhythmias, endocrinopathy and cognitive impairment (32). The range of severity is broad, with differences in repeat length being the key driver of disease severity. Table 5 depicts the relationship between CTG repeat length, age of onset and disease severity, including mild, classic and congenital forms of disease.

“Mild” disease may manifest simply with premature cataracts and baldness, with electromyographically detectable myotonia. “Classic” disease typically manifests in young adulthood and includes distal weakness, symptomatically and often disabling myotonia, as well as significant cardiac conduction defects in addition to cataracts and baldness.

Classic disease, when presenting in teen years, is also known as “juvenile” disease. “Congenital” DM1, in which the affected parent is nearly always the mother, is present at birth. The infant is floppy, facial and jaw muscles are weak resulting in failure to thrive, and mental retardation and development delay are common.

Rather than displaying myotonia, congenital DM muscles display features of arrested fiber development. Table 5 highlights that that some unaffected individuals have repeats in the “mutable normal” range of 35–49 repeats.

Such metastable alleles are prone to expand when transmitted to the next generation; new mutations in families arise through this process. Table 5 also illustrates overlap in the range of repeat lengths across these various classes. An important, life-threatening feature of DM1 is cardiac involvement which can lead to sudden cardiac death.

Repeat length and cardiac abnormalities also are correlated in DM1 (95). Genetic testing for the CTG expansion in DM1 is relatively straightforward. In less than 5% of DM1 patients, the CTG repeat is interrupted by other trinucleotides but the clinical and genetic significance since of these interruptions is unknown (68).

Table 5.

CTG repeat length/phenotype correlation in myotonic dystrophy type 1

PhenotypeClinical FeaturesRepeat SizeAge of Onset
Mutable normalNone35–49NA
Mild myotonia
50-~15020–70 years
Cardiac arrhythmia
~100-~100010–30 years
CongenitalInfantile hypotonia
Respiratory deficits
Intellectual disability
Classic signs develop later
~700- >1000Birth to 10 years

DM2 commonly presents as proximal muscle weakness with variable myotonia, hence its former name proximal myotonic myopathy (121). Like DM1, it too shows marked clinical heterogeneity ranging from mild forms of disease that may be difficult to detect, to profound and disabling proximal muscle weakness.

There is no congenital form of disease nor is there apparent anticipation. Cardiac involvement is less common in DM2 than in DM1 (118), but still requires careful monitoring. Whereas in DM1 cognitive impairment is well described (19,46), DM2 shows much less cognitive involvement (109).

The CCTG repeat expansion in DM2 is complex, including repeat elements in addition to the CCTG repeat, and is prone to an extreme range of pathogenic expansions, from 75 units to as many as 11,000 units (mean of roughly 5000 repeats) (68).

Despite this broad range, there is little evidence for correlation between repeat length and disease severity; reasons for this lack of relationship are currently unknown.

The molecular mechanism of disease may be as well worked out for DM1 as it is for any repeat expansion disease. The CTG expansion resides in the 3’UTR of the DMPK transcript, where it does not alter expression of the disease protein, but does form RNA foci and bind to and sequester essential splicing factors (69,110).

This toxic RNA effect leads to a failure to generate appropriately spliced isoforms of key muscle genes, leading to myotonia and other symptoms of disease. Loss of DMPK function is well tolerated in mouse models (21) and thus nucleotide-based gene-silencing approaches as potential disease-modifying therapy represent an attractive strategy for this disabling disorder (136). The pathogenic basis of DM2 is less clear, but leading candidates include a toxic RNA effect (e.g. 89).

CAG/polyglutamine diseases 

At least nine diseases belong to the CAG/polyglutamine group (11,58,70,74,77,99,105,114,122). These diseases are thoroughly described in four chapters in this volume: the polyglutamine diseases as a whole (chapter 11); SBMA (chapter 38); HD (chapter 17); and the SCAs (chapter 12). Here, I focus on shared features across the class as well as distinctive findings in specific disorders that shed light on disease mechanisms.

All nine are dominantly inherited disorders except for SBMA which is an X-linked disorder with dominant toxic features. All are classified as rare diseases. HD, the best known among them, is also the most common, with SCA3 next in line. Six are dominantly inherited ataxias (also known as SCAs) including the four most common SCAs among the 40 discovered thus far (SCAs 1,2,3,6).

A seventh disorder, DRPLA, can be thought of as a hybrid between SCA and HD. In all nine, the primary pathogenic mechanism is believed to be proteotoxicity emanating from the encoded disease protein (see Table 6).

Other than sharing a common glutamine repeat, the various disease proteins are entirely unrelated and serve very different cellular functions. The distinctive clinical and pathological features of individual CAG/polyglutamine diseases are believed to stem primarily from this differing protein context. At least two other repeat expansion diseases may share elements with the polyglutamine diseases: In SCA8, the antisense transcript can encode a polyglutamine protein through RAN translation, and the CAG repeat in SCA12 theoretically could encode polyglutamine though evidence supporting this is less clear.

Table 6.

Polyglutamine diseases and their encoded proteins

CAG/Polyglutamine DiseasesEncoded protein(s)Function
Huntington diseaseHuntingtinScaffold protein associated with autophagy
Spinal and bulbar muscular atrophyAandrogen receptorHormone-dependent transcription factor
Dentatorubral-pallidoluysian atrophyAtrophin-1Transcription cofactor
Spinocerebellar ataxia type IATXN1Transcription cofactor
Spinocerebellar ataxia type 2ATXN2RNA binding protein implicated in RNA homeostasis
Spinocerebellar ataxia type 3ATXN3Deubiquitinase
Spinocerebellar ataxia type 6CACNA1A subunit (Cav2.1)/α1ACTCalcium channel subunit/transcription factor
Spinocerebellar ataxia type 7ATXN7Component of SAGA acetyltransferase complex
Spinocerebellar ataxia type 17TATA Binding ProteinGeneral transcription factor

Figure 3 compares the normal and disease repeat lengths for the CAG/polyglutamine diseases. Several important features can be gleaned from the comparison. First, a repeat length of roughly 35–40 is a common disease threshold across polyglutamine disorders.

This repeat size conforms to in vitro biochemical studies showing that polyglutamine proteins begin to aggregate at roughly the same threshold. This is a relevant point because aggregation of the disease protein, particularly in neurons, is a common pathological hallmark of the polyglutamine disorders.

There are, however, important exceptions to this repeat length threshold. For example, SCA6 is caused by an expansion well below this threshold; it is also, however, the only CAG/polyglutamine disease in which the encoded protein is a trans-membrane protein, a calcium channel subunit.

Tethered close to the membrane, the glutamine repeat in SCA6 may be particularly sensitive to small changes in length. Recently, a second polyglutamine-containing protein was discovered to be expressed from the SCA6 locus, a transcription factor known α1ACT, raising another possibility for the basis of a shorter disease threshold: potentially profound effects of modest repeat expansions on transcription function.

In contrast, for SCA3 and SCA17, normal repeats exist that are even larger than the putative threshold of 35. The respective disease proteins in SCA3 and SCA17 are a deubiquitinase implicated in protein quality control (ATXN3) and an essential general transcription factor (TATA binding protein). Whether these proteins possess special properties that would permit a larger normal polyglutamine tract remains to be determined.

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Normal and disease repeat lengths for the CAG/polyglutamine diseasesNormal (green), incompletely penetrant (yellow) and fully penetrant (red) repeat lengths are shown for each disease. Deepening color of red illustrates increased disease severity and earlier age of onset with longer repeat lengths. Arrows illustrate that the longest disease repeats in spinocerebellar ataxia type 2 (SCA2), SCA7 and Huntington disease are >100 repeats. Gray regions represent size range of intermediate length repeats that may be prone to further expansion. High normal SCA2 alleles (orange) are a risk factor for ALS. At SCA1 locus, normal repeats can be longer when they are interrupted by CAT residues. DRPLA, dentatorubral-palliodoluysian atrophy; SBMA, spinobulbar muscular atrophy
* Normal repeat length in SCA1 and SCA6 are modifiers of age of onset, and SCA6 normal repeat length is also a modifier of age of onset in SCA2.
# In SCA2 disease repeats interrupted by CAA can be associated with dominantly inherited Parkinson disease rather than ataxia.
^ Normal repeat in SCA17 is an imperfect CAG repeat interrupted with CAA residues.

A second feature for many CAG/polyglutamine diseases is a narrow range of modestly expanded repeats for which disease is incompletely penetrant (colored yellow in figure 3). Clearly, factors other than the repeat length itself influence whether disease will become manifest.

A particularly telling example is SCA1, where perfect CAG repeats begin to cause disease at approximately 40 repeats, whereas CAG repeats interrupted by a histidine-coding CAT can extend several repeats further before causing disease.

The simplest hypothesis (not proven) is that the disease protein is stabilized when histidine interrupts the polyglutamine tract. For all polyglutamine diseases, in the fully penetrant repeat range, the smaller the expansion the wider the predicted potential age of symptom onset. In HD, for example, individuals with 40 repeats may experience their first disease symptoms in the 30s or 70s, whereas individuals with repeat length of 80 would always show signs of disease before age 30. Careful genetic analysis of HD individuals whose repeat lengths are near the lower end of the pathogenic range has identified additional genetic modifiers that influences age of onset (49).

Understandably, the study of polyglutamine disorders has focused on the expanded repeat, but insights have also been gained from studying the normal repeat. In both SCA6 and SCA1, the size of the normal repeat contributes modestly to age of onset (135a and b), and the size of the normal SCA6 repeat may be a modifier of disease onset in SCA2 (111).

Moreover, at the SCA2 locus, repeats at the high end of the normal range are an important genetic risk factor for ALS. Intriguingly, some SCA2 expansions can manifest with ALS (116,143) and SCA2 itself is characterized by motor neuropathy in addition to progressive ataxia.

The SCA2 protein, ATXN2, is an RNA binding protein implicated in stress granule dynamics and RNA/protein homeostasis, which are critically important pathways in ALS and presumably also in SCA2. This discovery underscores the point that, even in the normal range, repeat length variation influences the behavior of polyglutamine disease proteins.

Other repeat expansion SCAs 

At least four other SCAs are caused by repeat expansions. One of these, SCA12, is caused by a CAG expansion that may or may not encode polyglutamine, and at least one other, SCA8, can generate polyglutamine from the antisense strand.

Michigan Medicine


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