Posted by jayaram in The presence of reiterated three-base-pair DNA sequences has been noted in a number of human genetic diseases including fragile X syndrome, myotonic dystrophy, X-linked spinal and bulbar muscular atrophy (Kennedy’s syndrome), spinocerebellar ataxia, and Huntington’s disease. These diseases are associated with expansion of certain triplet nucleotide repeats that appear to be over represented in the human genome. Repeats can be present in different locations near or within the associated gene. In all cases, expansion of the triplet interferes with normal functioning of the protein. In many cases, a loss of protein function occurs, but in some cases, the gain of a deleterious function occurs.
Fragile X syndrome, a leading cause of mental retardation, is characterized by expansion of triplets are characterized by an increase in severity of the disease with each successive generation, which is known as anticipation. Normally, about 30 copies of this triplet are present on the 5’-side of a gene associated with the disease, the FMR-1 gene. The site of the repeat is expanded to as many as 300 copies in males that carry fragile X gene mutations but have no symptoms of the disease. Offspring of male carriers who express the disease can have a remarkable expansion of the triplet repeat, up to thousands of copies. The disease develops when normal expression of the FMR-1 gene is turned off. Methylation of CpG dinucleotides present in CGG triplets appears to be associated with shutting off the FMR-1 gene.
Triplet expansion may result from slipped mispairing during DNA synthesis. Because of massive amplification that characterizes the diseases associated with triplet expansion, repeated or multiple slippage would have to be involved to explain the high degree of expansion. One possible mechanism for expansion involves slippage of nascent DNA during lagging strand synthesis. This process may be aided by formation of a stable hairpin structure by the slipped loop. Repetition of this process leads to accumulation of large numbers of triplet repeats that result in disease.