DISEASES OF TRINUCLEOTIDE REPEATS A number of human loci have trinucleotide repeats. Expansion of some of these loci is harmless, however, expansion of many loci has grave consequences and leads to a variety of disorders such as Huntington's disease, myotonic dystrophy and some ataxias.These repeats have included the CGG, CAG and CTG sequences (Table 1). In the March 8, 96 issue of Science, Capmpuzano et al report a new type of repeat, GAA, that is associated with Friedrich's ataxia.There is a distinct difference in the diseases associated with the other repeats as compared with that associated with the Friedrich's ataxia. The former group of repeats are found in part of exons that may or may not code for an amino acid and result in disorders that are inherited as a dominant trait. The length of these repeats shows instability in the siblings of the family member who exhibits such an expanded repeat sequences. This so-called "dynamic mutations" gain additional repeats through generations. Friedrich's ataxia (FRDA) is distinct from the group of diseases with trinucleotide repeats that have so far been identified. This disease is transmitted as an autosomal recessive disorder that involves the central and peripheral nervous system. A gene, X25 was identified in the FRDA locus on chromosome 9q13 that encodes a 210 amino acid protein that is designated frataxin. A few FRDA patients had point mutations in the X25 gene, however, the majority of patients were homozygous for unstable GAA repeats in the first intron rather than the exon of the involved gene. The individuals who are heterozygotes for the disease carry the expanded alleles but are phenotypically normal. As compared with the carriers or normal controls, FRDA patients show either undetectable or low amounts of X25 transcript. The expanded trinucleotide sequences in the coding region of the genes of ataxias and the 5' untranslated region of FMR1 gene in the fragile X syndrome, and the intron of the gene implicated in the Friedrich's ataxia produce functional changes. It is likely that soon we will witness the discovery of other genetic disorders due to the repeat of the trinucleotide sequences as well as the mechanism that lead to the lengthening of such repeats. TABLE 1. DISEASES OF TRINUCLEOTIDE REPEATS SEQUENCE OF THE REPEAT LOCATION OF THE REPEAT _______________________________________________________________________________________ Fragile site 11B CGG EXON Fragile X syndrome _______________________________________________________________________________________ Dentatorubral-pallidoluysian atrophy CAG EXON Haw river syndrome Huntington's disease Machado-Joseph disease Spinal and Bulbar muscular dystrophy Spinocerebellar ataxia type 1 _______________________________________________________________________________________ Myotonic dystrophy CTG EXON _______________________________________________________________________________________ Friedrich's ataxia GAA INTRON _______________________________________________________________________________________