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Trinucleotide repeat disorders (also known as trinucleotide repeat expansion disorders or expansion disorders) are due to stretches of DNA in a gene that contain the same trinucleotide sequence repeated many times. These repeats are a subset of unstable microsatellite repeats that occur throughout all genomic sequences. If the repeat is present in a gene, an expansion of the repeat results in a defective gene product and often disease. 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 human beings.
Eight of these disorders have the same repeated codon, CAG, that codes for glutamine. These diseases are commonly referred to as polyglutamine diseases. The other six disorders do not have similar repeats and are classified as non-polyglutamine diseases. A common symptom of polyglutamine (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-polyglutamine diseases do not share any specific symptoms and are also unlike the polyglutamine diseases.
Trinucleotide repeat disorders generally show genetic anticipation, with milder forms becoming more severe among descendants.
Polyglutamine (PolyQ) Diseases
- Caused by the DRPLA gene on chromosome 12. The normal DRPLA allele has between 6 and 35 copies of CAG, however, in people with the disorder the allele has between 49 and 88 copies.
- HD (Huntington's disease)
- Caused by the DRPLA gene on chromosome 12. The normal DRPLA allele has between 6 and 35 copies of CAG, however, in people with the disorder the allele has between 49 and 88 copies.
- Caused by the huntingtin gene. The normal huntingtin allele has between 10 and 35 copies of CAG, however, in people with the disorder the allele has more than 40 copies.
- SBMA (Spinobulbar muscular atrophy or Kennedy disease)
- Caused by the huntingtin gene. The normal huntingtin allele has between 10 and 35 copies of CAG, however, in people with the disorder the allele has more than 40 copies.
- Caused by the Androgen receptor (AR) gene on the X chromosome. The normal AR allele has between 9 and 36 copies of CAG, however, in people with the disorder the allele has between 38 and 62 copies.
- SCA1 (Spinocerebellar ataxia Type 1)
- Caused by the Androgen receptor (AR) gene on the X chromosome. The normal AR allele has between 9 and 36 copies of CAG, however, in people with the disorder the allele has between 38 and 62 copies.
Non-Polyglutamine Diseases
- FRAXA (Fragile X syndrome)
- Caused by the FMR1 gene on the X-chromosome. The normal FMR1 allele has between 6 and 53 copies of CGG, however, in people with the disorder the allele has over 230 copies.
- FRAXE (Fragile XE mental retardation)
- Caused by the FMR1 gene on the X-chromosome. The normal FMR1 allele has between 6 and 53 copies of CGG, however, in people with the disorder the allele has over 230 copies.
- Caused by the FMR2 gene on the X-chromosome. The normal FMR2 allele has between 6 and 35 copies of GCC, however, in people with the disorder the allele has over 200 copies.
- FRDA (Friedreich's ataxia)
- Caused by the FMR2 gene on the X-chromosome. The normal FMR2 allele has between 6 and 35 copies of GCC, however, in people with the disorder the allele has over 200 copies.
- Caused by the X25 (frataxin) gene. The normal X25 allele has between 7 and 34 copies of GAA, however, in people with the disorder the allele has over 100 copies.
- DM (Myotonic dystrophy)
- Caused by the X25 (frataxin) gene. The normal X25 allele has between 7 and 34 copies of GAA, however, in people with the disorder the allele has over 100 copies.
- Caused by the DMPK gene. The normal DMPK allele has between 5 and 37 copies of CTG, however, in people with the disorder the allele has over 50 copies.
- SCA8 (Spinocerebellar ataxia Type 8)
- Caused by the DMPK gene. The normal DMPK allele has between 5 and 37 copies of CTG, however, in people with the disorder the allele has over 50 copies.
- Caused by the SCA8 gene. The normal SCA8 allele has between 16 and 37 copies of CTG, however, in people with the disorder the allele has between 110 and 250 copies.
- SCA12 (Spinocerebellar ataxia Type 12)
- Caused by the SCA8 gene. The normal SCA8 allele has between 16 and 37 copies of CTG, however, in people with the disorder the allele has between 110 and 250 copies.
- Caused by the SCA12 gene. The normal SCA8 allele has between 7 and 28 copies of CAG (in the 3' UTR and therefore does not translate to glutamine), however, in people with the disorder the allele has between 66 and 78 copies.
Trinucleotide repeat expansion
Trinucleotide repeat expansion, also known as triplet expansion, is the DNA mutation responsible for causing any type of disorder categorized as a trinucleotide repeat disorder. Triplet expansion is caused by slippage during DNA replication. The exact cause of this is unknown, but may involve secondary structure of DNA.
See also
"Trinucleotide repeat disorders"