Trinucleotide repeat disorder

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In genetics, trinucleotide repeat disorders, a subset of microsatellite expansion diseases (also known as repeat expansion disorders), are a set of over 30 genetic disorders caused by trinucleotide repeat expansion, a kind of mutation in which repeats of three nucleotides (trinucleotide repeats) increase in copy numbers until they cross a threshold above which they cause developmental, neurological or neuromuscular disorders.^[1][2][3] In addition to the expansions of these trinucleotide repeats, expansions of one tetranucleotide (CCTG)^[4], five pentanucleotide (ATTCT, TGGAA, TTTTA, TTTCA, and AAGGG), three hexanucleotide (GGCCTG, CCCTCT, and GGGGCC), and one dodecanucleotide (CCCCGCCCCGCG) repeat cause 13 other diseases.^[5] Depending on its location, the unstable trinucleotide repeat may cause defects in a protein encoded by a gene; change the regulation of gene expression; produce a toxic RNA, or lead to production of a toxic protein.^[1][2] In general, the larger the expansion the faster the onset of disease, and the more severe the disease becomes.^[1][2]

Trinucleotide repeats are a subset of a larger class of unstable microsatellite repeats that occur throughout all genomes.

The first trinucleotide repeat disease to be identified was fragile X syndrome, which has since been mapped to the long arm of the X chromosome. Patients carry from 230 to 4000 CGG repeats in the gene that causes fragile X syndrome, while unaffected individuals have up to 50 repeats and carriers of the disease have 60 to 230 repeats. The chromosomal instability resulting from this trinucleotide expansion presents clinically as intellectual disability, distinctive facial features, and macroorchidism in males. The second 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.^[6] The discovery that trinucleotide repeats could expand during intergenerational transmission and could cause disease was the first evidence that not all disease-causing mutations are stably transmitted from parent to offspring.^[1]

Trinucleotide repeat disorders and the related microsatellite repeat disorders affect about 1 in 3,000 people worldwide.^{[citation needed]} However, the frequency of occurrence of any one particular repeat sequence disorder varies greatly by ethnic group and geographic location.^[7] Many regions of the genome (exons, introns, intergenic regions) normally contain trinucleotide sequences, or repeated sequences of one particular nucleotide, or sequences of 2, 4, 5 or 6 nucleotides. Such repetitive sequences occur at a low level that can be regarded as "normal".^[8] Sometimes, a person may have more than the usual number of copies of a repeat sequence associated with a gene, but not enough to alter the function of that gene. These individuals are referred to as "premutation carriers". The frequency of carriers worldwide appears to be 1 in 340 individuals.^{[citation needed]} Some carriers, during the formation of eggs or sperm, may give rise to higher levels of repetition of the repeat they carry. The higher level may then be at a "mutation" level and cause symptoms in their offspring.

Three categories of trinucleotide repeat disorders and related microsatellite (4, 5, or 6 repeats) disorders are described by Boivin and Charlet-Berguerand.^[2]

The first main category these authors discuss is repeat expansions located within the promoter region of a gene or located close to, but upstream of, a promoter region of a gene. These repeats are able to promote localized DNA epigenetic changes such as methylation of cytosines. Such epigenetic alterations can inhibit transcription,^[9] causing reduced expression of the associated encoded protein.^[2] The epigenetic alterations and their effects are described more fully by Barbé and Finkbeiner^[10] These authors cite evidence that the age at which an individual begins to experience symptoms, as well as the severity of disease, is determined both by the size of the repeat and the epigenetic state within the repeat and around the repeat. There is often increased methylation at CpG islands near the repeat region, resulting in a closed chromatin state, causing gene downregulation.^[10] This first category is designated as "loss of function".^[2]

The second main category of trinucleotide repeat disorders and related microsatellite disorders involves a toxic RNA gain of function mechanism. In this second type of disorder, large repeat expansions in DNA are transcribed into pathogenic RNAs that form nuclear RNA foci. These foci attract and alter the location and function of RNA binding proteins. This, in turn, causes multiple RNA processing defects that lead to the diverse clinical manifestations of these diseases.^[2]

The third main category of trinucleotide repeat disorders and related microsatellite disorders is due to the translation of repeat sequenced into pathogenic proteins containing a stretch of repeated amino acids. This results in, variously, a toxic gain of function, a loss of function, a dominant negative effect and/or a mix of these mechanisms for the protein hosting the expansion. Translation of these repeat expansions occurs mostly through two mechanisms. First, there may be translation initiated at the usual AUG or a similar (CUG, GUG, UUG, or ACG) start codon. This results in expression of a pathogenic protein encoded by one particular coding frame. Second, a mechanism named "repeat-associated non-AUG (RAN) translation" uses translation initiation that starts directly within the repeat expansion. This potentially results in expression of three different proteins encoded by the three possible reading frames. Usually, one of the three proteins is more toxic than the other two. Typical of these RAN type expansions are those with the trinucleotide repeat CAG. These often are translated into polyglutamine-containing proteins that form inclusions and are toxic to neuronal cells. Examples of the disorders caused by this mechanism include Huntington's disease and Huntington disease-like 2, spinal-bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, and spinocerebellar ataxia 1–3, 6–8, and 17.^[2]

The first main category, the loss of function type with epigenetic contributions, can have repeats located in either a promoter, in 5'untranscribed regions upstream of promoters, or in introns. The second category, toxic RNAs, has repeats located in introns or in a 3' untranslated region of code beyond the stop codon. The third category, largely producing toxic proteins with polyalanines or polyglutamines, has trinucleotide repeats that occur in the exons of the affected genes.^[2]