Trinucleotide repeat disorders

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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 humans.

Eight of these disorders have the same repeated codon, CAG, that codes for glutamine (Q). These diseases are commonly referred to as polyglutamine ( or PolyQ) diseases. The other six disorders do not have similar repeats and are classified as non-polyglutamine diseases.

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.

Trinucleotide repeat disorders generally show genetic anticipation, where their severity increases with each successive generation that inherits them.

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.

1 Polyglutamine (PolyQ) Diseases
2 Non-Polyglutamine Diseases
3 Trinucleotide repeat expansion
4 See also

[edit] Polyglutamine (PolyQ) Diseases

DRPLA (Dentatorubropallidoluysian atrophy)

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 huntington gene. The normal huntington allele has between 10 and 35 copies of CAG, however, in people with the disorder the allele has more than 35 copies.

SBMA (Spinobulbar muscular atrophy or Kennedy disease)

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) wildtype CAG: 6-35; pathogenic CAG: 49-88
SCA2 (Spinocerebellar ataxia Type 2) wildtype CAG: 14-32; pathogenic CAG: 33-77
SCA3 (Spinocerebellar ataxia Type 3 or Machado-Joseph Disease) wildtype CAG: 12-40; pathogenic CAG: 55-86
SCA6 (Spinocerebellar ataxia Type 6) wildtype CAG: 4-18; pathogenic CAG: 21-30
SCA7 (Spinocerebellar ataxia Type 7) wildtype CAG: 7-17; pathogenic CAG: 38-120
SCA17 (Spinocerebellar ataxia Type 17) wildtype CAG: 25-42; pathogenic CAG: 47-63

[edit] 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 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 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 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 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 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.

[edit] Trinucleotide repeat expansion

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. Robert I. Richards and Grant R. Sutherland called these phenomena, in the framework of dynamical genetics, dynamic mutations. Triplet expansion is caused by slippage during DNA replication. Due to the repetitive nature of the DNA sequence in these regions 'loop out' structues may form during DNA replication while maintaining completmentary base paring between the parent strand and daughter strand being snythesised. 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 the 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 sympotoms to increase through successive generations of an affected family due to the expansion of these repeats.