Molecular Basis of Genetic Instability of Triplet Repeats (*)

A veritable explosion is taking place in our understanding of the human genetics, biochemistry, and DNA structural issues related to human hereditary neuromuscular and neurodegenerative diseases. Also, the non-Mendelian expansion process that elicits these disease manifestations (anticipation) is under intense investigation. Within the last 3 years, the molecular basis of 10 human genetic disorders (including fragile X syndrome (FRAXA and FRAXE), myotonic dystrophy (DM), Kennedy’s disease, Huntington’s disease (HD), spinocerebellar ataxia type 1 (SCA1), and dentatorubral-pallidoluysian atrophy (DRPLA)) has been partially established (reviewed in Refs. 1–5). The diseases are characterized at the molecular level by the expansion of a simple triplet repeat (CTG and CGG) from less than 15 copies of the repeat in normal individuals to scores of copies in affected cases; thousands of copies are found in some cases of fragile X and myotonic dystrophy. These increases in size occur upon passage of an expanded repeat in the chromosome to offspring. Moreover, the symptoms of these diseases follow an unusual genetic pattern called anticipation, in which the disease becomes more severe and has an earlier age of onset with each successive generation (reviewed in Refs. 1–6). The instability of repeats in the genome has also been linked to hereditary nonpolyposis colon cancer, which may involve mutations in mismatch repair functions (4, 5, 7–9). For example, Huntington’s disease shows anticipation and has expanded CAG triplet repeats (1–5, 10). A CAG repeat of between 11 and 34 bp in the normal population encodes a polyglutamine tract in the IT15 gene. Expansion to about 90 bp occurs in HD patients. The age of onset correlates with the length of the triplet repeat with the largest changes in repeat lengths seen upon paternal transmission (11). Sperm display a heterogeneous expanded repeat length. An intermediate allele, IA, containing 30–38 (or 34–38) repeats (perhaps similar to a premutation in fragile X or DM) has been identified. Initial reports suggest that sporadic expansion of the IA allele occurs only through paternal transmission (12, 13). The function of the gene product is uncertain (14). Considering Mendelian genetic principles, anticipation was an enigma. The discovery of expanding triplet repeats (or “mutable mutations”) in diseases showing anticipation afforded a physical basis for this unusual genetic phenomenon. Expansion of the triplet repeat is responsible for the genetic defect, influencing the activity of a glutamine-containing protein (SBMA, HD, SCA1, and DRPLA) or influencing the level of expression of a gene with which the repeat is associated (fragile X and DM) (1–5). All triplet repeat genetic diseases identified to date show anticipation. Several other diseases also show anticipation including spinocerebellar ataxia type 2 (15), bipolar affective disorder (16), and hereditary spastic paraparesis (Strumpell’s disease) (17). If a correlation exists between anticipation and triplet repeats, many more diseases showing anticipation may be identified since there are more than 40 genes containing associated triplet repeats.