Since the early 90’s, 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 that 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 normal persons. The chromosomal instability resulting from this trinucleotide expansion presents clinically as mental retardation, 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 GCC 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.
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.
The non-PolyQ diseases do not share any specific symptoms and are unlike the PolyQ diseases.
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.
|DRPLA (Dentatorubropallidoluysian atrophy)||ATN1 or DRPLA||6 - 35||49 - 88|
|HD (Huntington's disease)||HTT (Huntingtin)||10 - 35||35+|
|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+|
|FRAXE (Fragile XE mental retardation)||AFF2 or FMR2, on the X-chromosome||GCC||6 - 35||200+|
|FRDA (Friedreich's ataxia)||FXN or X25, (frataxin)||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||CAG On 5' end||7 - 28||66 - 78|
Triplet expansion is caused by slippage during DNA replication. Due to the repetitive nature of the DNA sequence in these regions, 'loop out' structures may form during DNA replication while maintaining complementary base paring between the parent strand and daughter strand being synthesized. 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. Generally 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 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.