The trinucleotide repeat disorders (also known as trinucleotide repeat expansion disorders or triplet repeat expansion disorders) are a set of genetic disorders caused by an increase in the number of trinucleotide repeats in certain genes exceeding the normal, stable, threshold. Each gene affected by trinucleotide repeat expansion has a different number of repeats that constitutes the normal threshold and the number that results in manifestation of disease.
The trinucleotide repeat disorders are divided into three categories determined by the type of repeat. The most common repeat is the triplet CAG which when present in the coding region of a gene codes for the amino acid glutamine (Q). Therefore, these disorders are referred to as the polyglutamine (polyQ) disorders. The second category of repeat expansion disorders either do not involve the CAG triplet in the coding region or the CAG triplet is not in the coding region of the gene or the triplet is not CAG and also is not in the coding region. This second type of trinucleotide repeat disorder is referred to as the non-polyglutamine disorder class. The non-polyglutamine disorders result from repeats (primarily trinucleotide repeats) that reside in the promoter region of the affected gene, within the 5'-untranslated region (5'-UTR), within introns, or within the 3'-UTR. The third category of trinucleotide repeat expansion disorder consists of the diseases associated with expansion of a polyalanine tract (PA) or alterations in genes harboring a polyalanine tract. There are currently 9 well characterized PA disorders in humans although there are close to 500 genes encoding proteins that harbor stretches of consecutive alanine residues ranging from 4 to 20 amino acids in length. One unique feature of the polyalanine repeat is that it is an imperfect repeat consisting of the nucleotides GCN, where N designates any nucleotide.
Although trinucleotide repeat expansion encompasses the vast majority of repeat expansion diseases, there are other diseases caused by repeat expansion where the repeat size is four (tetranucleotide), five (pentanucleotide), or 10 (dodecanucleotide) nucleotides in length. A second genetic cause of myotonic dystrophy, identified as myotonic dystrophy 2 (also identified as dystrophica myotonica 2, Ricker syndrome, or proximal myotonic myopathy) results from the expansion of the tetranucleotide CCTG. The CCTG repeat resides in the first intron of the zinc finger protein 9 (ZNF9) gene. The number of repeats found in the ZNF9 gene in affected individuals has been shown to range from a low of 75 to as many as 11,000. The particular form of spinocerebellar ataxia identified as type 10 (SCA10) results for the expansion of a pentanucleotide repeat (AATCT) that resides in intron 9 of the ataxin 10 (ATXN10) gene. The number of repeats found in the ATXN10 gene in affected individuals has been shown to range from 280 to well over 4,100. One form (EPM1A) of the family of at least ten disorders identified as epilepsy, progressive myoclonic results from the expansion of a dodecanucleotide repeat (C4GC4GCG) that resides in the promoter region of the cystatin B (CSTB) gene. In this latter disorder the size of the expansion in affected individuals ranges from 3–17 repeats.