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Review
. 2013:1010:3-17.
doi: 10.1007/978-1-62703-411-1_1.

A brief history of triplet repeat diseases

Helen Budworth  1 , Cynthia T McMurray
Affiliations
Review

A brief history of triplet repeat diseases

Helen Budworth et al. Methods Mol Biol. 2013.

Abstract

Instability of repetitive DNA sequences within the genome is associated with a number of human diseases. The expansion of trinucleotide repeats is recognized as a major cause of neurological and neuromuscular diseases, and progress in understanding the mutations over the last 20 years has been substantial. Here we provide a brief summary of progress with an emphasis on technical advances at different stages.

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Figures

Fig. 1
Fig. 1
Trinucleotide repeat expansion disorders caused by triplet repeats in coding and noncoding gene regions. (a) Inheritance of disease genes and parent–child transmission causes rapid expansion of repeat regions. (b) Triplet repeats residing in coding and noncoding sequences of a gene have significant impact on human health and underlie many severe neurological disorders
Fig. 2
Fig. 2
Pathophysiology of trinucleotide repeat disorders and effect of repeat number. Affected brain regions and regions of neuronal loss in neurological disorders associated with TNR expansion are shown on the left. Red regions indicate the major affected areas and areas of neuronal loss. In HD, patients with 36–120 CAG repeats are affected by the disease and show neuronal loss in regions of the brain that control movement. Schematic representations of affected genes are shown on the left. Repeat regions within each gene are indicated by the small bar in the coding region of the gene. The inverted triangle represents an increasing number of repeats. The base of the triangle represents unaffected individuals; dotted lines indicate unaffected carriers for disease, and the red part of the triangle indicates affected individuals. C/P caudate/putamen, CTX cortex, GP globus pallidus, STN subthalamic nucleus, VL ventrolateral thalamic nucleus, SN substantia nigra
Fig. 3
Fig. 3
Effects of CAG expansion in the huntingtin gene. A representative two-generation pedigree of an HD family. Squares are males; circles are females. Red boxes indicate affected individuals. Open circles are unrelated spouses. Black numbers represent CAG repeat number in each allele of the affected family members. Small black letters indicate the alleles present in father-to-son transmission. The number in brackets represents the size of the CAG expansion during inheritance. The relationship between HD and CAG repeat number (left). In this schematic representation of the HD gene, the open bar represents the coding region of the Huntington’s gene (called huntingtin); the small red bar indicates the position of the CAG repeat stretch located within the N-terminal portion of the coding sequence. The inverted triangle represents an increasing number of CAG repeats. The base of triangle represents unaffected individuals with 6–26 CAG repeats; lines indicate unaffected carriers for disease with 27–35 CAG repeats; and the top part of the triangle indicates affected individuals with 36–120 CAG repeats
Fig. 4
Fig. 4
Effect of repeat number on age of onset and anticipation. (a) Age of onset is inversely correlated with repeat number. Increasing CAG repeats in the HD disease gene decreases the age of onset of symptoms of the disease. Early onset/juvenile HD symptoms can be seen at repeat numbers above 60. (b) Anticipation phenotype in a three-generation family showing the increased severity in successive generations. Grandfather (left), symptoms of myotonia since age 50, but no significant disability. Mother (middle), myotonia since late teens. Son (right), congenital myotonic dystrophy
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