Anticipation, Premutation and Trinucleotide Repeat

Anticipation

This is often observed in disorders resulting from the expression of a trinucleotide repeat mutation Opens in new window in diseases such as Huntington’s disease Opens in new window and myotonic dystrophy Opens in new window. In these conditions, nucleotide runs of three are excessively repeated in the DNA Opens in new window. Thus they are called trinucleotide repeat disorders.

Trinucleotide Repeat

Trinucleotide repeats tend to increase in size and have a more significant effect when passed from one generation to the next. For example, a child with myotonic dystrophy may have severe hypotonia and failure to thrive, yet the affected grandfather has only early balding and presenile cataracts.

Most genes are transmitted unaltered through each generation of a family. In triplet repeat disorders, the triplet repeat is unstable once it reaches a critical size threshold, and the size can increase in successive generations. These unstable mutations are referred to as dynamic mutations (Sutherland and Richards, 1994).

It is normal to have fewer than a certain number of these trinucleotide repeats. The instability of the trinucleotide repeats tend to be related to their size (with longer repeats being more unstable and more likely to increase in size).

Rarely, contractions in size occur, and the contractions are usually small (LaSpada, 1994). Often repeats are transmitted unchanged with neither expansion nor contraction.

Premutation

Premutation describes an intermediate size range between trnucleotide repeats with sizes in the normal (stable) range and larger repeats in the range associated with disease.

Individuals who carry a premutation often have no symptoms of disease, mild symptoms of disease, or a later onset of disease than individuals with larger trinucleotide repeat expansions. Premutations are unstable and may expand into the full mutation range during meiosis.

For some trinucleotide repeat disorders, the stability of the mutation is influenced by the sex of the parent transmitting the mutation. Congenital myotonic dystrophy Opens in new window seems to be inherited primarily from the mother whereas childhood-onset Huntington disease Opens in new window occurs more often from the father.

The risk for severe childhood presentation is also correlated with the affected parent having a large trinucleotide repeat expansion. In fragile X syndrome Opens in new window, premutation carrier males cannot transmit a full mutation to their daughters, though all their daughters inherit the premutation. However, when the unstable fragile X mutation is transmitted by females, it often increases in size (with larger CGG repeats having a much higher risk of expansion in the offspring) (McConkie-Rosell et al., 2005).

A large trinucleotide repeat expansion is often associated with a more severe presentation of the disease (LaSpada, 1994; Nance, 1997). For example, in myotonic dystrophy Opens in new window, it is normal to have fewer CTG repeats.

In the premutation range between 38 and 49 repeats, the individual does not have symptoms of myotonic dystrophy. However, an expansion can occur in the egg or sperm of an unaffected premutation carrier; thus the person’s offspring are at risk to be affected (with milder symptoms often occurring with CTG repeats in the range of 50–80, and more severe symptoms associated with CTG repeats over 200).

An individual with 1,000 or more CTG repeats usually displays the severe congenital form of myotonic dystrophy (Harper, 2002). Huntington disease (HD) is an example of an autosomal dominant trinucleotide repeat disorder showing variable expressivity, age-related penetrance, anticipation, and parental bias in the stability of the trinucleotide repeat.