Nucleotide Expansion Diseases

Genetic Diseases, Trinucleotide Expansion Diseases

For most of the 20^th Century, human genes were thought of as stable, identical sequences passed from generation to generation. However, this all changed in 1991 when an unstable, expanded trinucleotide repeat was found to be responsible for fragile X syndrome. Since that time, over 40 neurological, muscular, and developmental disorders have been shown to result from the expansion of unstable nucleotide repeats, and the once unique mutational mechanism of nucleotide expansion had itself expanded into a new class of diseases.

Although there are now a number of known nucleotide expansion diseases, the trinucleotide repeat diseases (also known as triplet repeat diseases) are the most common. Information on four well-known trinucleotide repeat diseases, fragile X syndrome, Friedreich ataxia, myotonic dystrophy, and Huntington’s diseases, can be found in other posts, but first, it is helpful to understand what trinucleotide repeat diseases are and how they occur.

In trinucleotide repeat diseases, a segment of DNA that contains a repeat of three nucleotides (e.g. CAGCAG) either in the coding or non-coding region of a gene, can expand or contract as the gene is passed from generation to generation . The wild-type forms of these alleles are polymorphic and have variable but low numbers of tandem triplet units. It is not until the number of repeats expands beyond the normal range that disease occurs.

An important predictor of trinucleotide repeat expression is the length of triplet tract. As a rule, the longer the repeat tract is, the greater the propensity for expansion in subsequent generations and the more severe the disease.

Some alleles have a repeat tract that is only mildly longer than normal. Individuals with these alleles are often asymptomatic or are only mildly affected very late in life. These alleles are known as premutations. Premutations display some instability and risk expansion in transmission to the next generation. Thus, as premutations travel through successive generations, they become progressively larger, leading to genetic anticipation (the phenomenon in which disease symptoms are more severe and/or are evident at an earlier age with successive generations).

The occurrence of trinucleotide expansion diseases is often transmission biased. Since many premutations are more unstable in male transmission than female transmissions, most expansions are paternally inherited. This paternal bias is due to the fact that expansions occur most frequently during male gametogenesis. However, maternal transmission is predominant in a few diseases (such as fragile X syndrome). The disease causing allele is unstable both in somatic and germline cells and can result in some degree of somatic mosaicism for the number of repeats in different tissues from the same patient.

Although poorly understood, the biochemical mechanism by which trinucleotide repeat expansions are generated is likely to be similar for all the trinucleotide repeat diseases. The working hypothesis in this field is the formation of unusual DNA secondary structures, such as hairpin or slipped stranded structures, during DNA replication, repair, and recombination. In this proposed mechanism, DNA polymerase pauses while replicating through the triplet-repeat tract and momentarily dissociates. During reassociation, a misalignment between the template and the newly synthesized strand results in unpaired repeat sequences either on the template strand or on the newly synthesized strand, causing the addition or deletion of repeats. Misalignment is due to the formation of secondary structures (particularly hairpins) while the DNA is temporarily single stranded. If the template strand forms a hairpin, the lagging strand will replicate right across the hairpins, leaving out the nucleotides that formed the hairpin and, thereby, causing a contraction. However, if strand being synthesize (or an Okazaki fragment) forms a hairpin expansion of the repeat will occur because the nucleotides in the hairpin are “extra”. Studies have suggested that slippage and expansion occurs preferentially on the strand replicated by lagging-strand synthesis, perhaps because it is single stranded for a longer period of time and thus has more opportunity to engage in secondary structures.

Supporting this mechanism of expansion is the fact that certain repeats, including CTG, CAG, and CGG, are able form hairpin structures. These hairpin structures are predicted to protect the expansion from repair activities, including mismatch repair and flap endonuclease. In addition, repeat instability is dependent on the length of the repeat tract. This can be interpreted to mean that larger the number of repeats, the less stable and more likely to form a hairpin the mutant allele is.

Katie @ August 25, 2007