Genetics of childhood disorders: IX. Triplet repeat disorders.

Trinucleotide, or triplet, repeats consist of 3 nucleotides consecutively repeated (e.g., CAG CAG CAG CAG) within a region of DNA. All possible combinations of nucleotides are known to exist as triplet repeats, although some are more common than others. These repeated sequences are found both within gene boundaries and in the large stretches of DNA that lie benveen genes. If the triplet repeats lie within a gene, they may be found within the flanking upstream promoter region, within exons, or within introns. If they lie within exons, they may be present in the sequence that will be translated into protein. In that case, the repeat encodes a series of identical amino acids. The triplets may also occur at the 5’ or 3’ untranslated portion of the transcript. The different regions in which triplet repeats may lie are summarized in Figure 1. Thousands of trinucleotide repeats exist throughout the human genome. Many are the same length in d individuals, while others are of variable length. The variable, or polymorphic, repeats are almost always transmitted without change in length from one generation to the next. However, some do change in length when passed on, and when that occurs, the gene is often disrupted. This mutational type, first discovered in 1991, was termed a dynamic or expansion mutation. Over the past 8 years, more than a dozen diseases caused by trinucleotide repeat expansions have been identified. The discovery of this class of mutations has led to great excitement in the field of genetics, since expansion mutations often have properties contrary to the conventional wisdom of mendelian genetics. The currently known expansion mutation disorders fall into 3 general groups (Fig. 1). Eight diseases are caused by expanded CAG repeats encoding the amino acid glutamine. The best known and most thoroughly characterized member of this group is Huntington disease. The other members include spinocerebellar ataxia types 1, 2, 3, 6, and 7; dentatorubralpallidoluysian atrophy; and spinal and bulbar muscular atrophy. The repeated expansion occurs in different genes for each of these 8 disorders. However, for this group of disorders, the number of repeats at which the expansion is sufficient to cause disease is similar, typically about 40 triplets. Each disease within this first group is characterized by neurodegeneration in a particular set of cortical and subcortical brain regions. The pathology appears to result from neurotoxic properties of the excessively long stretches of glutamine residues encoded by the CAG repeat expansions. The clinical manifestations of these diseases, as exemplified by Huntington disease, may include abnormalities of voluntary and involuntary movement; dementia; affective, psychotic, or obsessivecompulsive symptoms; apathy; irritability; and other less specific personality changes. A second group of illnesses caused by relatively short repeat expansions consists of mostly developmental disorders. The