Genes with triplet repeats: a new class of mutations causing neurological diseases.
Microsatellites, simple tamdem repeats of 2 to 4 nucleotide sequences, are widely distributed throughout the genome. Trinucleotide repeats are found every 300 to 500 kb. Recently, a new type of mutation was described involving a specific expansion of triplets within or in close proximity to a gene. Expanded triplets have been found in the genes causing six different neurological disorders: fragile X syndrome (FRAXA), spinal and bulbar muscular atrophy (SBMA), myotonic dystrophy (DM), Huntington's disease (HD), spinocerebellar ataxia type 1 (SCA1), and dentato-rubra-pallidoluysian atrophy (DRPLA). These neurological disorders have in common a variable age of onset and clinical severity, as well as a decrease in the age of onset over generations, known as anticipation. These unusual characteristics are related to the observation that expanded repeats are unstable both in meioses and mitoses. A younger age of onset and an increase in severity correlate with a higher number of repeats. Interestingly, particular haplotypes are in disequilibrium with the mutation for FRAXA, DM and HD, suggesting instability for selected chromosomes. How expanded triplets affect the expression and the function of genes is still unknown. Since neurodegenerative disorders are often variable in age of onset and clinical severity, the list of expanding triplet mutations should increase in the very near future.
Plassart
E
E
INSERM U134, Hôpital de la Salpêtrière, Paris, France.
Fontaine
B
B
D004247:DNA; D005260:Female; D005600:Fragile X Syndrome / Q000235:genetics; D006801:Humans; D006816:Huntington Disease / Q000235:genetics; D008297:Male; D009134:Muscular Atrophy, Spinal / Q000235:genetics; D009154:Mutation; D009223:Myotonic Dystrophy / Q000235:genetics; D009422:Nervous System Diseases / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid; D013132:Spinocerebellar Degenerations / Q000235:genetics
D004247:DNA