Trinucleotide repeat disorder
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Trinucleotide repeat disorders (also known as trinucleotide repeat expansion disorders, triplet repeat expansion disorders or codon reiteration disorders) are a set of genetic disorders caused by trinucleotide repeat expansion, a kind of mutation where trinucleotide repeats in certain genes exceed the normal, stable threshold, which differs per gene. The mutation is a subset of unstable microsatellite repeats that occur throughout all genomic sequences. If the repeat is present in a healthy gene, a dynamic mutation may increase the repeat count and result in a defective gene.
Since the early 1990s, a new class of molecular disease has been characterized based upon the presence of unstable and abnormal expansions of DNA-triplets (trinucleotides). The first triplet disease to be identified was fragile X syndrome, which has since been mapped to the long arm of the X chromosome. At this point, there are from 230 to 4000 CGG repeats in the gene that causes fragile X syndrome in these patients, as compared with 60 to 230 repeats in carriers and 5 to 54 repeats in unaffected individuals. The chromosomal instability resulting from this trinucleotide expansion presents clinically as intellectual disability, distinctive facial features, and macroorchidism in males. The second, related DNA-triplet repeat disease, fragile X-E syndrome, was also identified on the X chromosome, but was found to be the result of an expanded CCG repeat. Identifying trinucleotide repeats as the basis of disease has brought clarity to our understanding of a complex set of inherited neurological diseases.
As more repeat expansion diseases have been discovered, several categories have been established to group them based upon similar characteristics. Category I includes Huntington's disease (HD) and the spinocerebellar ataxias that are caused by a CAG repeat expansion in protein-coding portions of specific genes. Category II expansions tend to be more phenotypically diverse with heterogeneous expansions that are generally small in magnitude, but also found in the exons of genes. Category III includes fragile X syndrome, myotonic dystrophy, two of the spinocerebellar ataxias, juvenile myoclonic epilepsy, and Friedreich's ataxia. These diseases are characterized by typically much larger repeat expansions than the first two groups, and the repeats are located outside of the protein-coding regions of the genes.
Currently, nine neurologic disorders are known to be caused by an increased number of CAG repeats, typically in coding regions of otherwise unrelated proteins. During protein synthesis, the expanded CAG repeats are translated into a series of uninterrupted glutamine residues forming what is known as a polyglutamine tract ("polyQ"). Such polyglutamine tracts may be subject to increased aggregation.
Recent results suggest that the CAG repeats need not always be translated in order to cause toxicity. Researchers at the University of Pennsylvania demonstrated that in fruit flies, a protein previously known to bind CUG repeats (muscleblind, or mbl) is also capable of binding CAG repeats. Furthermore, when the CAG repeat was changed to a repeating series of CAACAG (which also translates to polyQ), toxicity was dramatically reduced. The human homolog of mbl, MBNL1, which was originally identified as binding CUG repeats in RNA, has since been shown to bind CAG (and CCG) repeats as well.
These disorders are characterized by autosomal-dominant mode of inheritance (with the exception of spino-bulbar muscular atrophy, which shows X-linked inheritance), midlife onset, a progressive course, and a correlation of the number of CAG repeats with the severity of disease and the age at onset. Family studies have also suggested that these diseases are associated with anticipation, the tendency for progressively earlier or more severe expression of the disease in successive generations. Although the causative genes are widely expressed in all of the known polyglutamine diseases, each disease displays an extremely selective pattern of neurodegeneration.
Anita Harding was the first to identify the correlation between trinucleotide repeat expansion and diseases causing neurological dysfunction. At present there are 14 documented trinucleotide repeat disorders that affect humans.
A common symptom of PolyQ diseases is characterized by a progressive degeneration of nerve cells usually affecting people later in life. Although these diseases share the same repeated codon (CAG) and some symptoms, the repeats for the different polyglutamine diseases occur on different chromosomes.
The non-PolyQ diseases do not share any specific symptoms and are unlike the PolyQ diseases.
|Repeat count||Classification||Disease status|
|36–40||Reduced Penetrance||+/- Affected|
Trinucleotide repeat disorders generally show genetic anticipation, where their severity increases with each successive generation that inherits them. This is likely explained by the addition of further CAG-repeats in the gene in the progeny of affected individuals. For example, Huntington's disease occurs when there are more than 35 CAG repeats on the gene coding for the protein HTT. A parent with 35 repeats would be considered "normal" and never exhibit any symptoms of the disease. That parent's offspring, however, would be at an increased risk compared to the general population of developing Huntington's, as it would take only the addition of one more CAG codon to cause the production of mHTT (mutant HTT), the protein responsible for disease. Huntington's very rarely occurs spontaneously; it is almost always the result of inheriting the defective gene from an affected parent. That said, sporadic cases of Huntington's do occur, and those individuals with a parent who already has a significant number of CAG repeats in their HTT gene, especially if it approaches the number (36) required for the disease to manifest, are at an increased risk of developing Huntington's despite the lack of any history of the disease in their family. Also, the more repeats, the more severe the disease and the earlier its onset. This explains why individuals that have had Huntington's running in their family for a longer period of time show an earlier age of disease onset and faster disease progression, as mutations that add additional CAG codons become more likely with each successive generation.
Trinucleotide repeat disorders are the result of extensive duplication of a single codon. In fact, the cause is trinucleotide expansion up to a repeat number above a certain threshold level. Huntington's is a good example of this phenomenon, as can be seen in the table on the right.
Why three nucleotides?
An interesting question is why three nucleotides are expanded, rather than two or four or some other number. Dinucleotide repeats are a common feature of the genome in general, as are larger repeats (e.g. VNTRs - Variable Number Tandem Repeats). One possibility is that repeats that are not a multiple of three would not be viable. Trinucleotide repeat expansions tend to be near coding regions of the genome, and therefore repeats that are not multiples of three could cause frameshift mutations. If the frameshift mutations altered the expression of developmentally obligatory pathways, then non-trinucleotide repeats may be masked by developmental lethality. Mutations of 3 base pairs, on the other hand, do not cause a catastrophic frameshift mutation, and unless a stop codon (TAG, TAA, TGA) is the triplet that is added to the gene - which would in almost all cases render the protein coded for useless - a trinucleotide addition to a gene can have no effect at all on the protein, can cripple the protein, or sometimes can make it work even better than it used to. The overwhelming number of mutations are not beneficial, and this article is testimony to the severely detrimental effects trinucleotide additions to the genome can produce. Still, 3 (and multiples of 3) nucleotide expansions to a coding region of the genome are at least somewhat less likely to be detrimental to an organism as a maximum of two amino acids will be affected, and the reading frame otherwise maintained the same.
|This section requires expansion. (May 2008)|
In over half of these disorders, the repeated codon is CAG, which in a coding region, codes for glutamine (Q), resulting in a polyglutamine tract. These diseases are commonly referred to as polyglutamine (or PolyQ) diseases. The remaining disorders repeated codons do not code for glutamine and are classified as non-polyglutamine diseases.
Polyglutamine (PolyQ) Diseases
|Type||Gene||Normal PolyQ repeats||Pathogenic PolyQ repeats|
|DRPLA (Dentatorubropallidoluysian atrophy)||ATN1 or DRPLA||6 - 35||49 - 88|
|HD (Huntington's disease)||HTT (Huntingtin)||6 - 35||36 - 250|
|SBMA (Spinobulbar muscular atrophy or Kennedy disease)||Androgen receptor on the X chromosome.||9 - 36||38 - 62|
|SCA1 (Spinocerebellar ataxia Type 1)||ATXN1||6 - 35||49 - 88|
|SCA2 (Spinocerebellar ataxia Type 2)||ATXN2||14 - 32||33 - 77|
|SCA3 (Spinocerebellar ataxia Type 3 or Machado-Joseph disease)||ATXN3||12 - 40||55 - 86|
|SCA6 (Spinocerebellar ataxia Type 6)||CACNA1A||4 - 18||21 - 30|
|SCA7 (Spinocerebellar ataxia Type 7)||ATXN7||7 - 17||38 - 120|
|SCA17 (Spinocerebellar ataxia Type 17)||TBP||25 - 42||47 - 63|
|FRAXA (Fragile X syndrome)||FMR1, on the X-chromosome||CGG||6 - 53||230+|
|FXTAS (Fragile X-associated tremor/ataxia syndrome)||FMR1, on the X-chromosome||CGG||6 - 53||55-200|
|FRAXE (Fragile XE mental retardation)||AFF2 or FMR2, on the X-chromosome||CCG||6 - 35||200+|
|FRDA (Friedreich's ataxia)||FXN or X25, (frataxin—reduced expression)||GAA||7 - 34||100+|
|DM (Myotonic dystrophy)||DMPK||CTG||5 - 37||50+|
|SCA8 (Spinocerebellar ataxia Type 8)||OSCA or SCA8||CTG||16 - 37||110 - 250|
|SCA12 (Spinocerebellar ataxia Type 12)||PPP2R2B or SCA12||nnn On 5' end||7 - 28||66 - 78|
Trinucleotide repeat expansion
|This section requires expansion. (September 2011)|
Trinucleotide repeat expansion, also known as triplet repeat expansion, is the DNA mutation responsible for causing any type of disorder categorized as a trinucleotide repeat disorder. These are labelled in dynamical genetics as dynamic mutations.
Triplet expansion is caused by slippage during DNA replication. Due to the tandem repeats in the DNA sequence and the instability of the sequence in these regions, 'loop out' structures may form during DNA replication while maintaining complementary base pairing between the parent strand and the daughter strand being synthesized. In essence, a nick one side of the DNA strand is caused by cleavage by endonuclease whereby the repetitive triplet is extended and sealed by DNA polymerase and DNA ligase, respectively. If the loop out structure is formed from sequence on the daughter strand this will result in an increase in the number of repeats. However, if the loop out structure is formed on the parent strand, a decrease in the number of repeats occurs. It appears that expansion of these repeats is more common than reduction. In general, the larger the expansion the more likely they are to cause disease or increase the severity of disease. This property results in the characteristic of anticipation seen in trinucleotide repeat disorders. Anticipation describes the tendency of age of onset to decrease and severity of symptoms to increase through successive generations of an affected family due to the expansion of these repeats. In 2006, a model of expanding the triplets by involving RNA:DNA intermediate formed in repeat transcription or in post-transcription was proposed, and similar ideas turned to be an ongoing issue of mechanistic studies ever since. 
In 2007, a new disease model was produced to explain the progression of Huntington's Disease and similar trinucleotide repeat disorders, which, in simulations, seems to accurately predict age of onset and the way the disease will progress in an individual, based on the number of repeats of a genetic mutation.
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- Trinucleotide Repeat Expansion at the US National Library of Medicine Medical Subject Headings (MeSH)
- GeneReviews/NCBI/NIH/UW entry on DRPLA
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- MicroRNA, trinucleotide repeats and the genetics of general cognitive ability