CAG Repeats in SCA6

Molecular genetics has had a major impact on neurology. The genes for many neurodevelopmental and neurodegenerative disorders have been identified, and molecular diagnosis has replaced invasive and cumbersome diagnostic procedures. The hereditary ataxias may have benefited most from molecular studies. Genetic mapping and gene identification have classified these heterogeneous disorders, offered patients accurate diagnoses, and made genetic counseling feasible. In addition to these clinical benefits, exciting biological discoveries have been made possible by the molecular study of many neurologic diseases. For example, gene dosage of the peripheral myelin protein PMP22 is critical for peripheral nerve integrity and normal function¹; dynamic trinucleotide repeat mutations are the cause of numerous neurologic diseases²; and genes essential for normal development in Drosophila play critical roles in mammalian nervous system development.³ Among these discoveries, the expansion of trinucleotide repeats as a mutational mechanism has been one of the most intriguing breakthroughs. These unstable repeats have been found in both coding and noncoding regions of genes. The mechanisms by which expanded repeats cause disease vary depending on the position of the repeat within the respective gene. In fragile X syndromes(FMR1 and FMR2), the repeat interferes with normal transcription and translation of the gene, leading to loss of function of the protein.² In myotonic dystrophy, expansion of a CTG repeat in the 3′ untranslated region of the gene leads to disease most likely because of a dominant effect at the level of RNA.⁴ In Friedreich ataxia, the expansion of the GAA repeat in the first intron of the gene interferes with the transcription and translation of frataxin.² A number of neurodegenerative diseases, notably the dominantly inherited spinocerebellar ataxias (SCAs), share a common mutational mechanism: the modest expansion of a translated CAG repeat predicted to encode a polyglutamine tract.^{5,6 …}