Nucleotide Repeat Expansion Disorders

Several diseases are associated with an increase in the number of nucleotide repeats above a certain threshold . The repeats are sometimes located within the coding region of the genes, as in Huntington disease or the X-linked form of spinal and bulbar muscular atrophy (SBMA, Kennedy syndrome). In other instances, the repeats probably alter gene regulatory sequences.

If an expansion is present, the DNA fragment is unstable and tends to expand further during cell division. The length of the nucleotide repeat often correlates with the severity of the disease. When repeat length increases from one generation to the next, disease manifestations may worsen or be observed at an earlier age; this phenomenon is referred to as anticipation. In Huntington disease, for example, there is a correlation between age of onset and length of the triplet codon expansion. Anticipation has also been documented in other diseases caused by dynamic mutations in trinucleotide repeats . The repeat number may also vary in a tissue-specific manner. In myotonic dystrophy, the CTG repeat may be tenfold greater in muscle tissue than in lymphocytes .

Selected Trinucleotide Repeat Disorders

X-chromosomal spinobulbar muscular atrophy (SBMA)
Xq11-q12
CAG
XR
Androgen receptor

Fragile X-syndrome (FRAXA)         Fragile X-syndrome (FRAXE)
CGG                                                GCC
XR                                                   XR
FMR-1 protein                                 FMR-2 protein


Dystrophia myotonica (DM)
CTG
AD, variable penetrance
Myotonin protein kinase

Huntington disease (HD)
CAG
AD
Huntingtin

Spinocerebellar ataxia type 1 (SCA1)
CAG
AD
Ataxin 1

Spinocerebellar ataxia type 2 (SCA2)
CAG
AD
Ataxin 2

Spinocerebellar ataxia type 3 (SCA3); Machado Joseph disease (MD)
CAG
AD
Ataxin 3

Spinocerebellar ataxia type 6 (SCA6, CACNAIA)
CAG
AD
Alpha 1A voltage-dependent L-type calcium channel

Spinocerebellar ataxia type 7 (SCA7)
CAG
AD
Ataxin 7

Spinocerebellar ataxia type 12 (SCA12)
CAG
AD
Protein phosphatase 2A

Dentorubral pallidoluysiane atrophy (DRPLA)
CAG
AD
Atrophin 1

Friedreich ataxia (FRDA1)
GAA
AR
Frataxin