Microsatellite repeat instability and neurological disease

Abstract

Over 20 unstable microsatellite repeats have been identified as the cause of neurological disease in humans. The repeat nucleotide sequences, their location within the genes, the ranges of normal and disease-causing repeat length and the clinical outcomes differ. Unstable repeats can be located in the coding or the non-coding region of a gene. Different pathogenic mechanisms that are hypothesised to underlie the diseases are discussed. Evidence is given both from studies in simple model systems and from studies on human material and in animal models. Since somatic instability might affect the clinical outcome, this is briefly touched on. Available data and theories on the timing and mechanisms of the repeat instability itself are discussed, along with factors that have been observed to affect instability. Finally, the question of why the often harmful unstable repeats have been maintained throughout evolution is addressed.

Figure 1

Location of repeats within genes in relation to pathogenic mechanism. This schematic gene shows all microsatellite repeats described in this review, with their location within the gene. The colours indicate which pathogenic mechanism is thought to underlie the associated diseases. All repeats depicted above the gene are located in a coding sequence of the gene, while all repeats below are in non-coding regions. Please refer to the text and Table 1 for further information regarding these repeats, genes and associated disorders.

Figure 2

The prezygotic model of expansion of the fragile X mutation. This model assumes that an expansion of a maternal PM to an FM takes place during meiosis. The fertilised oocyte carries an FM allele. After separation from the embryo proper, the PGCs have an FM. Some alleles will contract to PMs. To explain why FMs are only transmitted through females, some selection must exist against FMs in the male germ line during spermatogenesis. In the mature testes, PM alleles predominate. In somatic cells and the female germ line, this selection does not take place. Cells with a PM are shown in green and cells with an FM are depicted in orange.

Figure 3

Replication fork progression and repeat instability. During normal replication, helicases break the hydrogen bonds that keep the two DNA strands together, which yield the replication fork. DNA polymerase can only synthesise a new strand in a 5′ to 3′ direction. Hence, on one strand (leading strand) DNA polymerase reads the DNA and adds nucleotides to the nascent strand in a continuous manner. On the other strand (lagging strand) the complementary strand is synthesised in short segments (Okazaki fragments) at a time, which are later joined together by DNA ligase. Formation of secondary structures, such as hairpins can form in one of the strands. This can impair normal replication fork processing. The sequence of the strands, together with the position of the origin of replication with respect to the repeat sequence, determine which strand is more prone to form hairpins. Whether a hairpin is present in the template or nascent strand, in turn determines whether contraction or expansion results in the next round of replication.